The Magic of Cubane!

 

File:Cuban.svgCubane[1]
Pentacyclo[4.2.0.02,5.03,8.04,7]octane
CAS 277-10-1

Cubane (C8H8) is a synthetic hydrocarbon molecule that consists of eight carbon atoms arranged at the corners of a cube, with one hydrogen atom attached to each carbon atom. A solid crystalline substance, cubane is one of the Platonic hydrocarbons. It was first synthesized in 1964 by Philip Eaton, a professor of chemistry at the University of Chicago.[2] Before Eaton and Cole’s work, researchers believed that cubic carbon-based molecules could not exist, because the unusually sharp 90-degree bonding angle of the carbon atoms was expected to be too highly strained, and hence unstable. Once formed, cubane is quite kinetically stable, due to a lack of readily available decomposition paths.

The other Platonic hydrocarbons are dodecahedrane and tetrahedrane.

Cubane and its derivative compounds have many important properties. The 90-degree bonding angle of the carbon atoms in cubane means that the bonds are highly strained. Therefore, cubane compounds are highly reactive, which in principle may make them useful as high-density, high-energyfuels and explosives (for example, octanitrocubane and heptanitrocubane).

Cubane also has the highest density of any hydrocarbon, further contributing to its ability to store large amounts of energy, which would reduce the size and weight of fuel tanks in aircraft and especially rocket boosters. Researchers are looking into using cubane and similar cubic molecules inmedicine and nanotechnology.

Synthesis

The original 1964 cubane organic synthesis is a classic and starts from 2-cyclopentenone (compound 1.1 in scheme 1):[2][3]

Scheme 1. Synthesis of cubane precursor bromocyclopentadienone

Reaction with N-bromosuccinimide in carbon tetrachloride places an allylic bromine atom in 1.2 and further bromination with bromine in pentane –methylene chloride gives the tribromide 1.3. Two equivalents of hydrogen bromide are eliminated from this compound with diethylamine in diethyl ether to bromocyclopentadienone 1.4

Scheme 2. Synthesis of cubane 1964

In the second part (scheme 2), the spontaneous Diels-Alder dimerization of 2.1 to 2.2 is analogous to the dimerization of cyclopentadiene to dicyclopentadiene. For the next steps to succeed, only the endo isomer should form; this happens because the bromine atoms, on their approach, take up positions as far away from each other, and from the carbonyl group, as possible. In this way the like-dipole interactions are minimized in the transition state for this reaction step. Both carbonyl groups are protected as acetals with ethylene glycol and p-toluenesulfonic acid inbenzene; one acetal is then selectively deprotected with aqueous hydrochloric acid to 2.3

In the next step, the endo isomer 2.3 (with both alkene groups in close proximity) forms the cage-like isomer 2.4 in a photochemical [2+2] cycloaddition. The bromoketone group is converted to ring-contracted carboxylic acid 2.5 in a Favorskii rearrangement with potassium hydroxide. Next, the thermal decarboxylation takes place through the acid chloride (with thionyl chloride) and thetert-butyl perester 2.6 (with t-butyl hydroperoxide and pyridine) to 2.7; afterward, the acetal is once more removed in 2.8. A second Favorskii rearrangement gives 2.9, and finally another decarboxylation gives 2.10 and 2.11.

The cube motif occurs outside of the area of organic chemistry. Prevalent non-organic cubes are the [Fe4-S4] clusters found pervasively iron-sulfur proteins. Such species contain sulfur and Fe at alternating corners. Alternatively such inorganic cube clusters can often be viewed as interpenetrated S4 and Fe4 tetrahedra. Many organometallic compounds adopt cube structures, examples being (CpFe)4(CO)4, (Cp*Ru)4Cl4, (Ph3PAg)4I4, and (CH3Li)4.

It was mentioned previously that cubane was first prepared in 1964 by Dr. Philip E. Eaton. He was partnered by Thomas W. Cole and together they successfully completed the first synthesis, shown schematically below:

N-bromosuccinimide acts as the reagent for a radical mediated allylic bromination reaction which is carried out in tetrachloromethane with heat as the initiatorBromine is added......and 2 moles of HBr are eliminated......and 2 moles of HBr are eliminated...

Reactive enough to undergo dimerisation via a [4+2] cycloaddition reaction to give the ENDO cycloadductThe more reactive, bridgehead ketone group is protected by Ketal formation.Photochemical energy is required to promote the [2+2] intramolecular cycloaddition reaction.

The acid mediated oxidation of the ktone group to a carboxylic acid.

 

 

The first occurance of a Hunsdiecker decarboxylation, firstly substitutes the caroxylic acid group and then removes it.The first occurance of a Hunsdiecker decarboxylation, firstly substitutes the caroxylic acid group and then removes it.

 

Acid hydrolysis releases the protected ketoneThe second instance of a Hunsdiecker decarboxylation.

 

The second instance of a Hunsdiecker decarboxylation.The second instance of a Hunsdiecker decarboxylation.

Decarboxylation via thermal degradation of di-t-butyl perester

 

This, however, was soon simplified by N.B.Chapman who condensed the process to give cubane-1,4-dicarboxylic acid in five steps and so cubane in six:

n 1966 J C Barborak et al discovered yet another new synthesis of cubane. It was slightly unconventional in the fact that it utilised cyclobutadiene as a key substance to the process. Before this,cyclobutadiene was usually unavailable for the purposes of organic chemistry due to it’s instability. The shorter synthesis is shown below:

Decomposition in presences of 2,5-dibromobenzoquinone gives......the endo adduct.

 

Irradiation, in benzene, with a mercury lamp initiates the intramolecular [2+2] cycloaddition reaction.

Treatment with KOH at 100 ºC gives the cubane-1,3-dicarboxylic acid

Decarboxylation via thermal degradation of di-t-butyl perester

Since the synthesis of the cubane-1,4-dicarboxylic acid has become shorter and easier, a new decarboxylation method has also devised to give increased yields of the final cubane product. This has allowed the scale of production reach multikilogram batches in places (Fluorochem in California and EniChem Synthesis in Milan) eventhough cubane and its derivatives remain expensive to purchase.

Cuneane may be produced from cubane by a metal-ion-catalyzed σ-bond rearrangement.[4][5]

Cubane is a unique molecule for its extraordinary C8 cage, very high symmetry,exceptional strain and unusual kinetic stability. The particular appeal of cubane,referred to as a landmark in the world of impossible compounds, stems from therehybridization of the carbon atoms away from the canonical sp3 configuration,that is required to bound together eight CH units in a cubic framework.There is now a revival of interest on the chemistry of cubane and its functionalized derivatives,triggered by potential applications as high-energy fuels, explosives and propellantsand intermediates in pharmaceuticalpreparations.Let us now discover the synthesis and properties of this landmark molecule of impossible chemistry
Cubanehas the highest strain energy (166kcal/mol) of any organiccompounds available in multi gram amount. It is a kineticallystable compound and only decomposite above 220 Celsius Degree.It is also one of the most dense hydrocarbons ever know.However, although many physical properties of cubane have been measured, in1980 and before, cubane was considered just a laboratory curiosity of interest only to academics.It changed, in early 1980s when Gilbert of U.S ArmyArmament and Development Command (now ARDEC) pointed out that cubane’svery high heat of formation and its exceptionally high density could make certain cubanederivatives important explosives.

The effectiveness of an explosive is dependent on the energentics of the decomposition reaction,

the number of moles and molecular weight of the gaseous products and also the density.

The more mols of of an explosive that can be packed into the limited volume the better. .

Highly nitrated cubanes can be predicted to be very dense and very powerful explosives.

Octanitrocubane is calculated to be 15~30%more powerful than HMX.

 

Cubane, which CA index name is Pentacyclo[4.2.0.02,5.03,8.04,7]octane (7CI,8CI,9CI),has exceptional structure, strain and symmetry and it is a benchmark in organic chemistry.It has been studied extensively and much of its properties has been published.Some of the physical properties are given at right hand table.

The C-C bond length is a bit longer than obtained in the original X-ray structure determination by

Fleischer in 1964. There is not much difference between this bond length and the

C-C bond length in a simple cyclobutane.

 

SYNTHESIS

The cubane system was first synthesized over 35 years ago by Philip Eaton and Tom Cole.
It is a highly symmetric cubic cage structure having carbon atoms at the vertices of a cube.
The synthesis needs to go through brombromocyclopentadienone
dimer I and cubane-1,4,dicarboxylic acid. It is a marvel scheme of economy and simplicity.
With only minor modification, this procedure remains to this day the best available

method for large-scale synthesis of cubane-1,4,dicarboxylic acid.

 

 

 

The stereospecific in situ [4 + 2] (Diels-Alder) cyclodimerization of 4-bromocyclo-pentadienone
is the key in this kinetically controlled synthesis. However, it is still a tricky matter
and a few years later after this synthesis is published, N.B.Chapman et al in England following up
this work and improved this synthesis.

Why cubane is stable?

The reason for this, unappreciated at the time of the early predictions of instability,

 is that there are no kinetically viable paths along which cubane can rearrange thermally.

 On one hand, orbital symmetry considerations raise the energy of concerted two-bond ring

opening reactions. On the

other, there is little to be gained by breaking just one bond as there is concomitantly

only a small change in geometry, and the resulting biradical is still very strained.

Functional group transformation

Functional groups on the cubane system generally behaves very well.Functional group transformation can be applied successfully.For example, the preparation of 1,4-dinitrocubane from cubane-1,4-dicarboxylic acid.(The mechanism is provided on the right hand side.) Classical methodology is used here.

Substitution on the cubane framework is fairly easy done by the cubyl radical.
However, the problem is such that a mixture of products are obtained.
Thus, to achieve controlled substitution on the cubane framework,
we need to carefully study the chemistry of the cubane system.

 

The improvement in synthesis of

cubane-1,4-dicarboxylic acid

 

 

This is the improved synthesis by N.B Chapman et al in England.

 Basically the improvement is such that the

2-bromocyclopentadienone could be made easily and undergoes spontaneous dimerization.

The rest of the reaction is the same as the original one.

 

This synthesis now is scaled up and is conducted in small pilot plants by

Flurochem in California and EniChem Synthesis in Milan.

This method is much more superior than the old method. It is introduced by

Derek Barton et al and use the radical-induced decomposition of diester which can be

prepared easily from cubane-1,4-dicarboxylic acid.

IMPROVEMENT

This method is much more superior than the old method. It is introduced by

Derek Barton et al and use the radical-induced decomposition of diester which can be

prepared easily from cubane-1,4-dicarboxylic acid

 

IR

 

Cubane is a colorless solid. It melts at 130- 131°C, and decomposes above the melting point.

 It is soluble in CS2, CC14, CHC13, and benzene.

Spectra were obtained from 400 to 3600 cm-l with a Beckman IR-12 spectrophotometer.

The lower limit was set by KBr cell windows. In addition a thick deposit of do was

 measured down to 200 cm-lin a Csl cell. Since no infrared bands were found, the range

200-400 cm-l was not examined for the other compounds.

The spectral slit widths were 1-2 cm-l in all cases.

In the infrared spectrum, there are only noticeable absorptions in the region from

 4000 to 660 cm-1appear at 300,1231, and 851 cm-1.

Generally, for single-line proton magnetic resonance spectrum, the one

and only absorption appears at chemical shift=6.0ppm.

Originally there was doubt whether cubane does exist.

The geometry at each carbon atom is far from tetrahedral.

Only later, we found out that there is no kinetically viable paths exist for

the thermal rearrangement of cubane.

At same time, orbital symmetry considerations shows that

the energy of concerted two-bond ring-opening reactions is very high.

There will be very little gain in energy by breaking just one bond, as the

concomitant change in geometry is small, and the resulting biradical is still very strained

In 1964 Fleischer showed that cubane forms a stable solid at room temperature with a

crystalline structure composed of cubane molecules occupying corners of the rhombohedral

primitive unit cell (space group R3). The cubic molecular geometry gives the solid many unusual

electronic,structural, and dynamical properties compared to the other hydrocarbons.

For example, solid cubane has a relatively high melting point temperature about 405 K! and a

very high frequency for the lowest-lying intramolecular vibrational

mode (617 cm-1). Recent work related to cubane has focused on solid cubane and cubane based

derivatives.Because of relatively weak intermolecular interaction the cohesive energy relative

to the constituent C8H8 is expected to be small, and most of the physical properties of

solid cubane are dominated by the properties of the C8H8molecule.

Pharmaceutical aspect of cubane

Because the cubane frame is rigid, substituent have precise spatial relationships to each another.

The distance across the cubane (the body diagonal) is almost the same as that between the para

positions of the benzene ring. On cubane, on can add substituents in the “benzene plane”, as

well as above and below it, so to speak. This offers fascinating position possibilities for

the synthesis of new pharmaceuticals. A number of cubane derivatives have already

been obtained which shows interesting activity in anti-AIDS and anti-tumor screens.

Although the activity or the toxicity balance of cubane is yet not know, the cubane

system is not inherently toxic. Most of cubanes are biologically innocuous.

The research of cubane pharmaceutical has just began. At least now,

cubane is a biologically stable, lipophilic platform on which the chemist

can install a wide range of substituents in a variety of well defined special relationships.

Developments in drug design programs should allow the judicious choice.

 

Dipivaloylcubane: a cubane derivatized with keto, cyano, and amide groups,

shown on the left- exhibits moderate activity against human immunodeficiency virus (HIV),

which causes AIDS, without impairing healthy cells.

Polymers of cubane:

Optically transparent cubanes and cubylcubanes have been proposed as building

blocks for rigid liquid-crystal compounds. UV active cubanes, for example cubyl ketones,

are readily transformed photochemically into coloured cyclooctatetraenes;this transformation

can be used to permanent information storage.

Another example of UV active cubane, which can be used to synthesis liquid crystals.

Polymers with cubane in the backbone or as a pendant group along a polymer chain is

focused now.

The cubane subunits in these polymers can be rearranged easily to cycloctatetraenes.

It is expected that polycyclooctatetra can be converted in to polyacetylenes by

the way of ring-opening metathesis polymerization. The polyacetylenes will have properties

which are enhanced by the chain being intrinsically part of another polymer.

These properties including stability and extrudability and etc. A example is shown below:

 

Cubane derivative could be the structural basis for a class of intrinsic small gap polymers.The small gap polymer could present intrinsic good conductivity without doping,good nonlinear optical and photoelectric properties.Investigation of oligamers with up to six units of a conjugated unsaturated cubane derivative,where all the hydrogen were removed, is carried out.The table below shows that the gap values in eV by EHT and PM3.These values suggest to us that these structures could be used to design a newclass of polymers with very small gap.

Explosive and fuels:

In the early 1980s Everett Gilbert of the U.S. Army Armament Research and Development

Command (now ARDEC) pointed out that the nitrocarbon octanitrocubane (ONC),

then unknown, has a perfect oxygen balance, and in light of the properties of the

parent hydrocarbon cubane should have a very high heat of formation per CNO2 unit

and an exceptionally high density as well. His colleagues Jack Alster, Oscar Sandus

and Norman Slagg at ARDEC provided theoretical support for Gilbert’s

brilliant insight and estimated that ONC would have a detonation pressure

significantly greater than HMX. Later, both statistical and computational

approaches predicted a density of 2.1 ± 2.2 g /cm3 for octanitrocubane,

greater than any other C, N, O compound.

Is Cubane a really good explosives?

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Numerous nitro compounds are employed commonly as military and commercial explosives.

There is a continuing search for more powerful and less shock-sensitive examples.

Such materials are also sought as potentially useful fuels and propellants.

Most interest is focused on high-density organic compounds that contain all of the

elements needed for combustion to gaseous products in the absence of air.

Nitrocubanes carrying five or more nitro groups contain enough oxygen to oxidize

all constituent carbon and hydrogen atoms to gaseous CO, CO2, or H2O.

Each of these, along with N2, “explodes” from the solid to 12 gaseous molecules.

The expansion from the dense solid to a lot of gas (much expanded by the released heat)

produces the desired effect in propellants and explosives. ONC has a “perfect”

oxygen balance and would produce (were the detonation completely efficient)

eight molecules of carbon dioxide and four of dinitrogen. As ONC has no

hydrogen, no water forms when it burns; when used as propellants such zero-hydrogen

compounds leave little or no visible smoke (steam) in the plume behind the rocket;

such “low-signature” rockets are difficult to track.

On application of the Kamlet and Jacobs equations led ARDEC to predict that

octanitrocubane would be a very much better explosive (Table 1) than the classic

C-nitro compound trinitrotoluene (TNT), perhaps 15±30% better than the nitramine

HMX (the most powerful, commonly used military explosive), and at least competitive

with (and perhaps less shock-sensitive than) the newest experimental explosive CL-20

 

 

SYNTHESIS:(1)

The high strain that the cubane framework is under has already been highlighted. The researchers had to very cautiously attach a nitro group to each of the corners of the cube in order to make the desired product. The insertion of the first four nitro groups could be done by manipulating functional groups:

The key intermediate, cubane-1,3,5,7- tetracarboxylic acid (TNC), was obtained by clever application of the Brown-Kharasch photochlorocarbonylation to cubane mono-acid.

The addition of four further nitro groups proved far more difficult and new methodologies had to be developed, specifically the process of interfacial nitration. This method was used successfully to convert the sodium salt of TNC to pentanitrocubane (PNC) and then hexanitrocubane (HNC), both are stable materials.

Interfacial nitration, however, proved deficient for further nitration of HNC and again new experimental methodology had to be developed for its successful conversion to heptanitrocubane (HpNC):

Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at -78°C gave the long-sought ONC:

 DIFF TYPES

For the last planned post in my Unnatural Products series, I’m going to write about Eaton’s 1981 synthesis of pentaprismane.[A] At the time, unnatural hydrocarbons were hot targets, and as the next largest prismane on the list this target was the subject of much research by groups around the world. Perhaps Eaton’s biggest rivals were the groups of Paquette and Petit, and in fact all three had, at various times, synthesised hypostrophene as an intended precursor to the target.

Unfortunately, the ‘obvious’ [2 + 2] disconnection from pentaprismane turned out to be a dead end and the photochemical ring closure was unsuccessful. The 1970s and early 1980s saw the publication of a number of other similarly creative, but sadly ill-fated, approaches based on various ring contractions, and the compound gained a well-earned reputation for extraordinary synthetic inaccessibility.

Eaton’s route began, as with the cubane and dodecahedrane syntheses previously covered in this series, with a Diels-Alder reaction. The diene used was the known tetrachlorocyclopentadienone acetal shown that upon heating neat with benzoquinone produced the endo adduct shown in excellent yield. Next, an even higher yielding photochemical [2 + 2] reaction was used to close the cage-like structure by cyclobutane formation. Treatment with lithium in liquid ammonia simultaneously reduced both ketones and removed all four chlorine atoms. The resulting diol was converted to the ditosylate, which, under carefully controlled conditions with sodium iodide in HMPA, underwent a mono-Finkelstein reaction to give the iodotosylate shown. When this was treated with t-BuLi halogen-lithium exchange, followed by an extraordinary fragmentation, gave a diene reminiscent of hypostrophene shown above. However, the extra carbon atom in the skeleton made all the difference, and unlike the parent compound, this did undergo a [2 + 2] cycloaddition when exposed to UV light. Finally, acetal hydrolysis gave homopentaprismane in 34% yield from benzoquinone, putting the group a single ring contraction from victory.[B]

With significant amounts of homopentaprismanone in hand, the group now intended to employ the transformation that had been the cornerstone of their cubane synthesis – the Favorskii rearrangement. Unfortunately, this required the introduction of a leaving group in the ketone α-position, a transformation made incredibly difficult due to the strained system and Bredt’s rule, which prevented enolisation.[C] Eventually a six-step sequence (!) to introduce a tosyloxy group was devised, beginning with a Baeyer-Villiger reaction using m-CPBA. A remarkable CH oxidation with RuO4, generated in situ, then gave the hydroxylactone. Treatment of this with diazomethane gave the corresponding δ-ketoester in almost quantitative yield. The group then reformed the starting norbornane-like bridge through use of an unusual acyloin type reaction effected by treatment with sodium in liquid ammonia. Finally, oxidation of the secondary alcohol and tosylation gave the Favorskii precursor, apparently preparable in muti-gram quantities.

Treatment with aqueous potassium hydroxide solution effected Favorskii rearrangement in excellent yield, especially considering that this was the first time the elusive pentaprimane ring system had been prepared. Finally, Eaton used the three-step decarboxylation he had developed for cubane to remove the extraneous acid and give pentaprismane in 18 steps. Awesome.[D]

References and suchlike

  1. A    J. Am. Chem. Soc., 1981, 103, 2134. Much like Eaton’s seminal cubane paper, the title is a single word, ‘Pentaprismane’. I love the lack of hype.
  2.  B   Although Petit had prepared this compound a full decade earlier, his approach relied on a cycloaddition of the difficult to prepare cyclobutadieneiron tricarbonyl with the acetal of tropone, and proved difficult to scale  up. In fact, in his own paper Eaton rather directly described it as ‘conceptually fascinating [but] useless synthetically’.
  3. C   Eaton uses the phrase ‘invasion at the bridgehead’, which I find delightfully evocative. Makes it sound like a second world war campaign. Apparently the group initially planned, in spite of Bredt’s rule, to deprotonate the bridgehead position, relying on inductive stabilisation of the anion rather than enolate formation, but were unable to do so.
  4. D  Pentaprismane is the most recent of three prismanes synthesised to date, the other two being cubane, and triprismane. Although I think triprismane looks quite silly, it was actually synthesised some 8 years previouslyby T. J. Katz in far fewer steps. Go figure.

 

The Amide Activating Group

 

The very first step of cubane frame substitution will be the activation of the cubane frame.

This can be done by amides. The idea is derived from the similarities between cubane and arenes.

 Both of them have C-H bonds with enhanced s character ( see structure),

 and in both the adjacent (ortho) substituents are forced to be coplanar.

A more specific example is the cubane-N,N-diisopropyl carboxamide

 reacts with excess lithium tetramethylpiperidide (LiTMP) in THF solvent.

About 3% of the deuteriation products obtained.

The diisopropyl amide activating group is used because it is inert to the amide

bases employed for ortho metalation. Although there is a problem, there is

 difficulty in hydrolyzed it the corresponding carboxylic acid.

The problem is finally solved by using borane reduction followed by the oxidation

 of the amine so produced with dimethyldioxirane or potassium permanganate (in large scale).

Transmetalation is the basis of a complete synthetic methodology for the preparation

of a great variety of the substituted cubanes.

In order to make the substitution productively, a way must be found to

make use of the small amount of anion in the equilibrium with the starting material.

Mercury salt is used here as an effective anion trap and very little starting material remain unreacted.

The mercury for lithium transmetalation resulted in nearly complete conversion of the

starting material by drawing the lithiation equilibrium to the right.

 

The amide group is important in stabilizing the intermediate lithiated cubane,

but not the mercuriated compound. Once the lithium is replaced by mercury,

 the amide group is again able to assist removal of another ortho-hydrogen atom.

In the end, the complex ortho-mercurated product mixture obtained was

 simplified by treatment with elemental iodine.

The iodine cleavage of the carbon-mercury bonds 2-iodo and 2,6-diiodo derivatives

of the starting amide in72% and 15% respectively

Cubyl Grignard Reagents

From transmetalation, a reverse transmetalation was also developed, which is basically adding Grignard reagent to the mercuriated cubane instead of the iodine. However, these processes have a great main disadvantage, the mercury is highly toxic. Thus, scale up of this method was limited.

In 1988, Bashir-Hashemi introduced transmetaltion with magnesium salts and thereby provided easy access to cubyl mono-and bis-Grignard reagents. It is a reaction of cubane diamide with an excess of LiTMP/MgBRin THF and quenching with I2 gave diiodocubane diamide of 72% yield.

The effect of the presence of electron withdrawing group     –  Cyanide

When electron withdrawing group such as cynate present, they stabilize both intermediate lithiated cubanes very well. As a result, only a small amount of LiTMP is need to achieve fairly complete deprotonation even at -78°C.

The inductive effect of the cyano group clearly enhances the reaction. However, the adding of cyano groups results in competitive lithiation and a mixture of products. However, this problem can be well trackled by adding MgBr2.The product ratio was improved to 9:1 favoring carboxyliation ortho to the amide function.

A mixture of product formed.

Increased selectivity by adding MgBr2

Since the reactivity of cubane metalation is enhanced greatly with presence of cyano groups, it is possible to substitute all three positions ortho to the amide in a simple reaction. For instance, 4-cyanocubanamide can be converted directly into the tri(tert-butylcarbonyl)derivative as shown below.

Through Baeyer-Villiger oxidation, ter-butyl cuybl ketones can be converted easily to the polycarboxyliated cubane.

PHENYL CUBANE

 

From the basis idea of cubyl Grignard Reagent, phenyl cubane can be synthesised. The reaction of cubane diamide with 10 equiv of LiTMP and 4.0 equivalents of MgBr2 etherate in THF at 0°C followed by the addition of 10.0 equiv of bromobenzene, gave diphenylcubane diamide in 53% yield.

The mechanism is shown below:

 

The benzyne intermediate was formed in situ from the reaction of excess of LiTMP with bromobenzene. For a similar reaction, MeMgBr is used and give 30% yield of bromo-phenylcubane diamide, the first cubane derivative containing 3 different substituents.

Now, let us look the main concern of the cubane derivatives–the nitrocubanes.

Nitrocubanes are sought to be powerful, shock-insensitive, high-density explosives. They are stable compounds with decomposition points above 200°C. Simple nitrocubane can be made from simple oxidation of amines( See Functional Group Transformation.)

If we want to add more nitro groups into the cubane nucleus, we cannot do it though transmetalation because there is unstoppable cage cleavage reactions when make adjacent nitro groups. The ab initio calculation has confirmed this destabilising effect.

We are going to discuss how to make more and more substituted nitrocubane until octanitrocubane(ONC), the ultimate power house, is synthesised.

 

1,3,5 trinitrocubane and 1,3,5,7 tetranitrocubane(TNC)

As we mention early, addition of nitro groups cannot be done through direct transmetalation. Thus, we need found some indirect route.

This is done by introducing a substituent on each of 3 ortho carbons and remove the ortho-activating group in the end.

By adding a electron-withdrawing group such as a cyano group will help the case here. This choice of original substituent is important here and when cyano group is chosen, it activates the cubane nucleus without affecting the ortho directing by the diamide (for details please refer to electron-withdrawing group-cyanite).

When the dicyano amide was treated with TMPMgBr in THF and quenched with CO2. The ortho (to amide) carboxylic acid was the only product.

Even when the much activated tricyanoamide is treated with TMPMgBr and CO2 ,again, the ortho position ( to amide) carboxylic acid was formed.

The removal of the carboxamido group is done through a smart yet tedious process. The cyano group is converted to acid group first. Then, it is reduced to alcohol by lithium aluminium hydride. At same time, the carboxamido is reduced to aminotetrol. The alcohols are protected as acetates and amino tetrol is converted to carboxylic acid. The carboxylic is then removed through Barton Decarboxylatio. A detail mechanism is provided below.

The cubane-1,3,5,7-teracarboxylic acid is converted to TNC on the mechanism as follow:

The whole process is very clever, but it is very long. Thus, in 1997, a improved synthesis method for TNC was proposed by making use of the photochemsitry.

Improved synthesis for TNC

In 1993, Bashir-Hashemi showed the cubane-1,3,5,7-tetracarboxylic acid chloride can be formed by applying photochemically induced chlorocarbonyl cation( the Kharasch_Brown Reaction).

For a fast reaction, a high power Hanovia of 450 watts, medium pressure Hg was used. The favoured products are cubane tetraacid chloride shown on the right hand side. The first one, cubane-1,3,5,7-tetracarboxylic acid, made up 30% overall. This reaction conveniently prepare us the important versatile intermediate .

A detail conversion process is provided below:

 

A catalyst TMSN3 is used in converting tetraacid chloride to tetracylazide. The rest is the same as the orginal reaction.

TNC is a thermodynamic powerhouse but remarkly stable kinetically. Figure 1 shows that rapid thermal decomposition doesnot start until over 250°C.

The literature was unsupportive of this optimistic view. Poor results were also obtained initially with nitrating agent such as NO2BF4, acetyl nitrate, amyl nitrate etc.

Tetranitrocubylsodium can be formed directly on treatment of TNC with sodium bis(trimethylsilyl) amide in THF at -75°C. It can react with electrophiles to provide a useful and convenient way to achieve further functionalization of cubane nucleus.

More substituted nitrocubanes-

Pentanitrocubane(PNC) and Hexanitrocubane(HNC)

PNC

Base on the property of tetranitrocubylsodium, nitryl chloride(NO2Cl) was used to further nitrate the cubane nucleus. Treatment of NO2Cl with tetranitrocubylsodium in THF at -75°C works out 10-15% yield of pentanitrocubane(PNC). The yield increased to 30% when the solution was frozen to-180°C and allowed to warm slowly. This is called the interfacial nitration process. It is suggested that NO2Cl oxidized tetranitrocubylsodium to a radical, which made the whole reaction worked.

Base on the property of NO2Cl , N2O4 should be a better choice. The results showed that it is actually a better with 60:40 PNC to TNC ratio. The reaction is extremely clean.

PNC is colourless and highly crystalline. It is the first nitrated cubane to contain adjacent nitro groups. It behaves just TNC and other nitrocubanes, remarkly stable kinetically.

HNC

Although HNC can be prepared the same way as PNC, but the separation between PNC and HNC is extremely difficult.

However, if TIPS-substituted PNC( by N2O4 nitration from TIPS-sub TNC) react with potassium base (K(TMSN)2and the nitration with N2O4 gave a mixture of (triisopropyl) HNC and PNC in 60:40 ratio. This step is important and crucial. The separation is now possible by column chromatography on silica gel. 30% isolated yield of PURE HNC could be obtained when further treated with SiO2.

Synthesis for the last two nitro cubanes- heptanitrocubane and octanitrocubane

Interfacial nitration is not sufficient to further nitration for heptanitrocubane. Al though it is very good in deed, we need to find something which can successfully convert heptanitrocubane (HpNC).

HpNC

In this procedure TNC was treated with at least 4 equivalents of the base NaN(TMS)2 (where TMS = trimethylsilyl) at ±78 C in 1:1 THF/MeTHF. After the mono sodium salt had formed, the solution was cooled to between ±125 and ±130°C giving a clear, but very viscous fluid. This was stirred vigorously as excess N2O4 in cold isopentane was added. After one minute, the base was quenched, and the whole mixture was added to water. This resulted reproducibly in almost complete conversion of TNC (1 g scale) to HpNC (95% by NMR), isolated crystalline in 74% yield!

ONC

However, even in the presence of excess nitrating agent (N2O4 or many others) no indication
of any formation of ONC was ever seen. It is suspected that anion nitration with N2O4 proceeds by oxidation of the carbanion to the corresponding radical.Perhaps the anion of HpNC is too stabilized for this to occur. (HpNC is significantly ionized in neutral methanol.) This concept led to the use of the more powerful oxidant nitrosyl chloride. Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at 78° C followed by ozonation at 78° C gave the long-sought ONC in 45±55% isolated yield on millimole scale. The intermediate product prior to oxidation is thought to be nitrosoheptanitrocubane.

Finally, the magic molecule, the so called the impossible molecule, octanitrocubane was synthesised. But, how good are they and how useful are they? Let us discuss about it in the following section.

Properties of nitrocubane:

Neither HpNC nor ONC is detonated by hammer blows!
Both have decomposition points well above 200 C. Octanitrocubane
sublimes unchanged at atmospheric pressure at 200 C. HpNC forms beautiful, colorless, solvent-free crystals when
its solution in fuming nitric acid is diluted with sulphuric acid. Single-
crystal X-ray analysis confirmed the assigned structure and
provided an accurate density at 21 C of 2.028 g cm±3, impressively
high for a C, H, N, O compound. Although octanitrocubane
catches the imagination with its symmetry, heptanitrocubane
currently is significantly easier to make than ONC. It is
denser, and it may be a more powerful, shock-insensitive explosive
than any now in use. According to page 41 of a 2004 IUPAC guide, cubane is the “preferred IUPAC name.”

  1.  ‘ ‘Cubaneand Thomas W. Cole. Philip E. Eaton and Thomas W. Cole J. Am. Chem. Soc.1964; 86(15) pp 3157 – 3158; doi:10.1021/ja01069a041.
  2.  The Cubane System Philip E. Eaton and Thomas W. Cole J. Am. Chem. Soc.1964; 86(5) pp 962 – 964; doi:10.1021/ja01059a072
  3.  Michael B. Smith, Jerry March, March’s Advanced Organic Chemistry, 5 th Ed., John Wiley & Sons, Inc., 2001, p. 1459. ISBN 0-471-58589-0
  4.  K. Kindler, K. Lührs, Chem. Ber., vol. 99, 1966, p. 227.

http://cst-www.nrl.navy.mil/lattice/struk/c8h8.html.

http://www.ch.ic.ac.uk/local/projects/b_muir/Enter.html.

http://www.sciencedirect.com.

http://www.sciencenews.org/.

http://www.winbmdo.com/.

Bashir-Hashemi, A., New developments in cubane chemistry: phenylcubanes.

J. Am. Chem. Soc.;1988;110(21);7234-7235, 110(21), 7234-7235.

D.S.Calvao, p. m. v. b. B. A. C. J. a., Theooretical Characterization of oligocubane.

Synthetic Metals 102 (1999) 1410.

E. W. Della, E. F. M., H. K. Patney,Gerald L. Jones,; Miller, a. F. A.,

Vibrational Spectra of Cubane and Four

of Its Deuterated Derivatives.

Journal of the American Chemical Society / 101.25 / December 5, I979,7441-7457.

Galasso, V., Theoretical study of spectroscopic properties of cubane.

Chemical Physics 184 (1994) 107-114.

Kirill A. Lukin, J. L., Philip E. Eaton,*,Nobuhiro Kanomata,Juirgen Hain,Eric Punzalan,and

Richard Gilardi, Synthesis and Chemistry of 1,3,5,7-Tetranitrocubane Including

Measurement of Its Acidity, Formation of o-Nitro Anions, and

the First Preparations of Pentanitrocubane and Hexanitrocubane.

J. Am. Chem. Soc., Vol. 119, No. 41, 1997,9592-9602.

P.E.Eaton, Cubanes: starting Materials For the chemistry of 1990s and the New Century.

J. Am. Chem. Soc.;1992;31;1421-1436, 31, 1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane

. J. Am. Chem. SOC.1993,115, 10195-10202.

Philip E. Eaton, R. L. G.; Zhang, a. M.-X., Polynitrocubanes: Advanced High-Density,

High-Energy Materials**. Adv. Mater. 2000, 12, No. 15, August 2.

Philip E. Eaton, Cubane: Starting Materials for the chemistry of the 1990s and the new century.

Angew.Chem.Int.Ed.Engl.1992,31,1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane.

J. Am. Chem. SOC., Vol. 115, No. 22, 1993,10196-10202.

T. YILDIRIM, P. M. G., D. A. NEUMANN, P. E. EATONC and ‘T. EMRICK’, SOLID

CUBANE: A BRIEF REVIEW. Carbon Vol. 36, No. 5-6, pp. 809-815,1998.

Zhang, P. E. E. a. M.-X., Octanitrocubane: A New Nitrocarbon.

Propellants, Explosives, Pyrotechnics 27, 1 – 6 (2002).

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Curcumin: A Spice Against Alzheimer’s

Polymeric nanoparticles encapsulating curcumin improve memory and cognitive functions in a rat model of Alzheimer disease

Curcumin: A Spice Against Alzheimer’s

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A New Class of Anti-AIDS Drugs?

By blocking HIV-mediated destruction of immune cells, the caspase 1 inhibitor VX-765 shows promise as a new AIDS therapy

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A New Approach to Malaria Treatment?

A New Approach to Malaria Treatment?

Halogenated natural alkaloids show herbicidal and antiplasmodial activity

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Chinese Plant Compound , Triptolide Wipes out Cancer in 40 Days, Say new Research.

Chinese Plant Compound , Triptolide Wipes out Cancer in 40 Days, Say new Research.

File:Triptolide.png

Triptolide is a diterpenoid epoxide found in the Thunder God Vine, Tripterygium wilfordii. It has in vitro and in vivo activities againstmouse models of polycystic kidney disease[1] and http://en.wikipedia.org/wiki/Pancreatic_cancer” rel=”nofollow”>pancreatic cancer, but its physical properties limit its therapeutic potential.[2] Consequently, a synthetic prodrugminnelide, is being studiedclinically instead.[2]

A little-known plant with a truly bizarre name is now making headlines as a cancer killer, with the compound of the plant vanishing tumors in mice with pancreatic cancer. Known as the ‘thunder god vine’ or lei gong teng, the Chinese plant is actually integrated into Chinese medicine and has been used for ages in remedying a number of conditions including rheumatoid arthritis.

According to the new research out of the University of Minnesota’s Masonic Cancer Center, the thunder god plant compound led to no signs of tumors after a 40 day period — even after discontinuing the treatment. Published in the journal Science Translational Medicine

http://stm.sciencemag.org/content/4/156/156ps21.full?sid=5203733d-ae1d-438e-9d36-b8bd9f16cd8d

Pancreas Cancer Meets the Thunder God

  • Sunil R. Hingorani and
  • John D. Potter

Sci Transl Med 17 October 2012 4:156ps21. DOI:10.1126/scitranslmed.3004956

…minnelide) of a natural product (triptolide) that has been shown to have potent…rheumatoid arthritis patients ( 4 ). Triptolide, a diterpenoid triepoxide, was first…show an excess of lymphomas) ( 9 ). Triptolide inhibits proliferation and/or induces…
Pancreatic Cancer A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer 

  • Rohit Chugh,et al

Sci Transl Med 17 October 2012 4:156ra139. DOI:10.1126/scitranslmed.3004334

…characterized. One component of T. wilfordii, triptolide, has shown promising effects against…malignancies-are desperately needed, but triptolide is poorly soluble in water and thus…synthesize a water-soluble form of triptolide, Minnelide, and demonstrate efficacy…

and funded by the National Institutes of Health, even the scientists working on the project were stunned by the anti-cancer properties of the compound. Known to contain something known as triptolide, which has been identified as a cancer fighter in previous research, it is thought to be the key component that may be responsible for the anti-tumor capabilities.

http://thearrowsoftruth.com/wp-content/uploads/2012/10/thunder-god-vine-stalk_medium-300×199.jpg” width=”300″ height=”199″ />

And just like with numerous other powerful substances like turmeric and ginger, mainstream science is still slowly confirming what many traditional practitioners have known for their entire lives. This is, of course, due to the fact that there is simply no moneyfor major corporations in researching the healing powers of natural herbs and compounds such as the compound found in the thunder god vine. Turmeric and ginger, for example, have been found to be amazing anti-cancer substances that are virtually free compared to expensive and dangerous cancer drugs.

References

Triptolide
Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.
‘If you liked this post, say thanks by sharing it or mail me amcrasto@gmail.com, all content is academic.
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Breast Cancer Drugs in Late-Stage Development/Recently Approved

 

The article is 2012-2013 based and reader discretion is sought to ascertian the stage of approval

Breast Cancer Drugs in Late-Stage Development/Recently Approved

 

Afinitor® (everolimus)

http://newdrugapprovals.wordpress.com/2013/04/27/drug-spotlight-afinitor-everolimus-novartis/

Sponsor: Novartis

Method of Action: Mammalian target of rapamycin (mTOR) inhibitor

Indications/Phase of Trial: Hepatocellular carcinoma; human epidermal growth factor receptor 2-positive (HER2+) breast cancer first-line and second-line; lymphoma; nonfunctional carcinoid tumor (Phase III; all new indications)

Approved in July in U.S., EU for advanced hormone-receptor-positive (HR+) and human epidermal growth factor Receptor 2-negative (HER2-) metastatic breast cancer with exemestane in postmenopausal women who have already received certain other medicines for their cancer

Approved earlier for adults with pancreatic neuroendocrine tumors (PNET) that cannot be treated with surgery; adults with advanced renal cell carcinoma (RCC) when certain other medicines have not worked; adults with angiomyolipoma, seen with tuberous sclerosis complex (TSC), when surgery is not required immediately; and adults and children with TSC who have a brain tumor called subependymal giant cell astrocytoma (SEGA) that cannot be removed completely by surgery

 

Avastin (Bevacizumab; RG435)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-has-approved-a-new-use-of-avastin-bevacizumab-in-combination-with-fluoropyrimidine-based-irinotecan-or-oxaliplatin-chemotherapy-for-people-with-metastatic-colorectal-cancer-mcrc/

Sponsor: Roche/Genentech

Method of Action: Monoclonal antibody; Vascular endothelial growth factor (VEGF) inhibitor

Indications/Phase of Trial: U.S.: Relapsed ovarian cancer, platinum-sensitive (Registration); first-line metastatic breast cancer and first-line metastatic ovarian cancer (both Phase III).

EU: Relapsed platinum-resistance ovarian cancer (Phase III)

Metastatic colorectal cancer, treatment beyond progression (Registration); adjuvant breast cancer, HER2- and HER2+; adjuvant NSCLC; first-line glioblastoma (GBM) multiforme; high-risk carcinoid (all Phase III)

Approved for metastatic colorectal cancer (mCRC) when started with the first or second intravenous 5-FU–based chemotherapy for metastatic cancer; advanced nonsquamous non-small-cell lung cancer (NSCLC) with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease; metastatic RCC (mRCC) with interferon alfa; and GBM in adult patients whose cancer has progressed after prior treatment. Effectiveness based on tumor response, as no data have shown whether Avastin improves disease-related symptoms or survival in people previously treated for GBM

Approval conditionally granted in 2008 and withdrawn November 2011 for HER2- metastatic breast cancer (mBC) with Paclitaxel

 

Buparlisib (BKM120)

Sponsor: Novartis

Method of Action: Pan-PI3K inhibitor

Indications/Phase of Trial: mBC (Phase III and confirmatory Phase I/II); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- locally advanced or mBC which progressed on or after aromatase inhibitor (AI) treatment (Phase III; BELLE-2 study recruiting as of November 2012); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- AI-treated, locally-advanced or mBC who progressed on or after mTOR inhibitor-based treatment (Phase III; BELLE-3 study, recruiting as of October 2012); with Paclitaxel in patients with HER2- inoperable locally advanced or mBC, with or without PI3K pathway activation (Phase III; BELLE-4 study, recruiting as of November); metastatic castration-resistant prostate cancer (CRPC; Phase II; recruiting as of October); recurrent glioblastoma (Phase II; recruiting as of November); recurrent/metastatic head and neck squamous cell carcinoma (Phase II; recruiting as of October); endometrial cancer (Phase I/II); NSCLC (Phase I/II); prostate cancer (Phase I/II); GBM multiforme (Phase I/II); with Fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer (Phase I); previously treated advanced colorectal cancer (Phase I)

 File:Fulvestrant.svg

Faslodex (Fulvestrant Injection)

Sponsor: AstraZeneca

Method of Action: Estrogen receptor antagonist

Indications/Phase of Trial: First line HR+ mBC (Phase III; FALCON study commenced Oct. 29)

Approved for HR+ mBC in women who have experienced menopause and whose breast cancer has worsened after they were treated with antiestrogen medications

 

Herceptin (Trastuzumab; RG597)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-approves-kadcyla-ado-trastuzumab-emtansine-a-new-therapy-for-patients-with-her2-positive-late-stage-metastatic-breast-cancer/

Sponsor: Roche, in partnership with Halozyme

Method of Action: Humanized monoclonal antibody designed to target and block the function of HER2+

Indications/Phase of Trial: EU: Early HER2+ breast cancer, subcutaneous formulation (Registration)

Approved for early-stage HER2+ breast cancer that has spread into the lymph nodes, and HER2+ breast cancer that has not spread into the lymph nodes and is estrogen receptor/progesterone receptor-negative (ER-/PR-) or have one high-risk feature. High-risk is defined as estrogen receptor/progesterone receptor-positive (ER+/PR+) with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3. Can be used with Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), and either Taxol® (paclitaxel) or Taxotere® (docetaxel); or with Taxotere and Paraplatin® (carboplatin); or alone after treatment with multiple other therapies, including an anthracycline (Adriamycin)-based chemotherapy

Also approved alone for the treatment of HER2+ breast cancer in patients who have received one or more chemotherapy courses for metastatic disease; and with paclitaxel for first-line treatment of HER2+ mBC

 

Iniparib (Tivolza; BSI-201; SAR240550)

Sponsor: Sanofi, through acquisition of original developer BiPar Sciences

Method of Action: Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor

Indications/Phase of Trial: Stage IV squamous NSCLC (Phase III; NME); solid tumors such as sarcoma and breast, uterine, lung, and ovarian cancers (Phase I/II)

Phase III trial in breast cancer failed January 2011 by failing to improve survival and progression-free survival (PFS) in breast cancer patients

 

Nexavar® (Sorafenib)

http://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

Sponsor: Onyx Pharmaceuticals

Method of Action: Dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases

Indications/Phase of Trial: Liver cancer adjuvant (Phase III; STORM study); kidney cancer adjuvant (Phase III; SORCE/ASSURE study); thyroid cancer monotherapy (Phase III; DECISION study); breast cancer with capecitabine (Phase III; RESILIENCE study)

Approved for hepatocellular carcinoma (HCC) and RCC

 

Perjeta (Pertuzumab; RG1273)

http://newdrugapprovals.wordpress.com/2013/03/05/the-european-medicines-agency-ema-has-approved-roches-perjetatm-pertuzumab-for-patients-with-previously-untreated-her2-positive-metastatic-breast-cancer-mbc/

Sponsor: Roche/Genentech

Method of Action: HER2/neu receptor antagonist

Indications/Phase of Trial: EU: With Herceptin and docetaxel chemotherapy for previously-untreated HER2+ mBC or locally recurrent, inoperable breast cancer in patients who have not received previous treatment or whose disease has returned after treatment in the early-stage setting (Registration)

U.S.: Approved June 2012 for HER2+ mBC with Herceptin (trastuzumab) and docetaxel, in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

Switzerland: Approved August 2012 for HER2+ breast cancer with Herceptin (trastuzumab) and docetaxel in patients with advanced or locally recurring breast cancer that has not previously been treated with chemotherapy

 

Ridaforolimus (MK-8669; AP23573; formerly Deforolimus)

http://newdrugapprovals.wordpress.com/2013/03/05/phase-3-breast-cancer-ridaforolimus-mk-8669-ap23573-formerly-deforolimus-merck-licenseariad-pharmaceuticals/

Sponsor: Merck, under exclusive worldwide license agreement with Ariad Pharmaceuticals

Method of Action: Oral inhibitor of mammalian target of rapamycin inhibitor (mTOR)

Indications/Phase of Trial: Maintenance therapy for metastatic soft-tissue sarcoma and bone sarcomas after at least four chemotherapy cycles (under review after receiving Complete Response letter from FDA in June; NME); breast cancer with exemestane, compared to breast cancer with dalotuzumab and exemestane (Phase II; recruiting as of November); advanced head and neck cancer, NSCLC and colon cancer, with cetuximab (Phase II); pediatric patients with advanced solid tumors (Phase I; recruiting as of September); with dalotuzumab in pediatric patients with advanced solid tumors (Phase I; recruiting as of August); advanced RCC, with vorinostat (Phase I; recruiting as of October 2012); breast cancer, with dalotuzumab (Phase I: recruiting as of September); endometrial and ovarian cancers, with paclitaxel and carboplatin (Phase I; recruiting as of September 2012); advanced cancer, with MK-2206 and MK-0752 (Phase I: recruiting as of September 2012); advanced cancer, with dalotuzumab, MK-2206 and MK-0752 (Phase I: recruiting as of August 2012)

 

Tivozanib (ASP4130; AV-951)

Sponsor: Aveo Oncology and Astellas

Method of Action: Tyrosine kinase inhibitor; inhibits VEGF receptor 1, 2, and 3

Indications/Phase of Trial: U.S.: Advanced RCC (Registration; NDA filed September 2012); tivozanib biomarkers in solid tumors (Phase II; BATON study); stage IV metastatic colorectal cancer (mCRC), with mFOLFOX6, and compared with bevacizumab and mFOLFOX6 (Phase II; recruiting as of November); additional data as first-line therapy for advanced RCC, followed by sunitinib (Phase II; TAURUS study, enrollment initiated in October 2012); advanced solid tumors, with capecitabine (Xeloda®; Phase I; recruiting as of October)

EU: Advanced RCC (Phase III)

 

Trastuzumab-DM1 (T-DM1; Trastuzumab emtansine; RG3502)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-approves-kadcyla-ado-trastuzumab-emtansine-a-new-therapy-for-patients-with-her2-positive-late-stage-metastatic-breast-cancer/

Sponsor: Roche, with linker technology developed by ImmunoGen

Method of Action: Antibody-drug conjugate, consisting of the antibody trastuzumab and the chemotherapy DM1 attached via a stable linker

Indications/Phase of Trial: U.S.: HER2+, unresectable locally-advanced or mBC who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy (Registration; Priority review approved Nov. 7; action date Feb. 26, 2013)

EU: Marketing Authorization Application for HER2+ mBC accepted for review by European Medicines Agency

 File:Lapatinib.svg

Tyverb/Tykerb (lapatinib)

http://newdrugapprovals.wordpress.com/2013/06/17/patent-of-fresenius-kabi-oncology-ltd-novel-intermediates-and-process-for-the-preparation-of-lapatinib-and/

Sponsor: GlaxoSmithKline

Method of Action: Human epidermal growth factor receptor-2 (Her2) and epidermal growth factor receptor (EGFR) dual kinase inhibitor

Indications/Phase of Trial: mBC with trastuzumab (Registration); breast cancer, adjuvant therapy (Phase III); Gastric cancer (Phase III); head & neck squamous cell carcinoma, resectable disease (Phase III)

 

Xgeva (denosumab)

http://newdrugapprovals.wordpress.com/2013/06/14/fda-approves-xgevadenosumab-to-treat-giant-cell-tumor-of-the-bone/

Sponsor: Amgen, with commercialization by GlaxoSmithKline in countries where Amgen has no presence

Method of Action: Fully human monoclonal antibody that specifically targets a ligand known as RANKL that binds to a receptor known as RANK

Indications/Phase of Trial: Delay or prevention of bone metastases in breast cancer (Phase III); delay or prevention of bone metastases in prostate cancer (Phase III)

Approved for prevention of fractures in men with advanced prostate cancer

Rejected in April for supplemental Biologics License Application to treat men with CRPC at high risk of developing bone metastases

 

Yondelis® (trabectedin)

Sponsor: Johnson & Johnson; developed in collaboration with PharmaMar

Method of Action: Binds to minor groove of DNA, interfering with the cell division and gene transcription processes, as well as DNA’s repair machinery

Indications/Phase of Trial: U.S.: Locally advanced or metastatic soft tissue sarcoma excluding leiomyosarcoma and liposarcoma who have relapsed or are refractory to standard-of-care treatment (Phase III; recruiting as of November); soft tissue sarcoma, excluding liposarcoma and leiomyosarcoma (L-type sarcoma), in previously-treated patients who cannot be expected to benefit from currently available therapeutic options (Phase III; recruiting as of November); locally advanced or metastatic L-sarcoma (liposarcoma or leiomyosarcoma) who were previously treated with at least an anthracycline and ifosfamide-containing regimen, or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen, compared with dacarbazine group (Phase III; recruiting as of November); breast cancer and pediatric tumors (Phase II); Advanced malignancies and liver dysfunction (Phase I; recruiting as of November)

EU: Approved for advanced or metastatic soft tissue sarcoma, and for relapsed platinum-sensitive ovarian cancer, with DOXIL®/Caelyx®

 

Xtandi® Capsules (Enzalutamide; formerly MDV3100)

http://newdrugapprovals.wordpress.com/2013/05/28/astellas-pharma-and-medivation-have-announced-the-submission-of-application-for-marketing-approval-of-enzalutamide-in-japan-for-the-treatment-of-prostate-cancer/

Sponsor: Medivation in collaboration with Astellas

Method of Action: Androgen receptor inhibitor

Indications/Phase of Trial: Prechemotherapy CRPC in patients who have failed luteinizing hormone-releasing hormone (LHRH) analog treatment only, as well as patients who have failed both LHRH analog and anti-androgen treatment. (Phase III; PREVAIL study); prostate cancer neoadjuvant therapy (Phase II); prechemo metastatic prostate cancer in Europe (Phase II; TERRAIN); prechemo metastatic and nonmetastatic prostate cancer patients in U.S. (Phase II; STRIVE); prostate cancer Hormone-naïve (Phase II; ASPIRE); prostate cancer with docetaxel (Phase I); breast cancer (Phase I)

EU: Marketing Authorization Application submitted June 2012 to European Medicines Agency, for patients with metastatic CRPC who have received docetaxel-based chemotherapy

Japan: Metastatic CRPC who have received docetaxel-based chemotherapy (Phase II)

Approved Aug. 31 for patients with metastatic CRPC who have previously received docetaxel. As a post-marketing requirement, Medivation and Astellas agreed to conduct an open-label safety study of Xtandi (160 mg/day) in patients at high risk for seizure, with data to be submitted to FDA in 2019

Links

 

 

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Greek Herbs- Fennel (saunf)

 
Fennel, otherwise known as Foeniculum vulgare, is a plant belonging to the genus Foeniculum. The fennel plant is native to the Mediterranean region, and the plant produces yellow flowers. Fennel is also an edible plant considered both aromatic and flavorful. In addition to culinary uses, fennel has several purported medicinal uses. Fennel powder is the powdered form made by grinding the seeds from the plant. Health supplement manufacturers use the fennel powder to produce fennel health supplements. You should, however, speak with your doctor prior to using fennel as a health
supplement.

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History of Fennel

Ancient Greeks and Indian cultures used fennel for cooking and as part of traditional herbal medicine. The Greeks and Indians traditionally combined fennel with other herbs to make home remedies for the relief of gastrointestinal problems such as acidity and indigestion.

Fennel Composition

The essential oil of fennel contains approximately 5 percent limonene, 50 to 80 percent anethole and 5 percent fenchone. Additionally, the oil contains trace amounts of a-pinene, estragole, b-pinene, safrole, b-myrcene, camphene and p-cymene. The seeds from the fennel plant also contain fiber and complex carbohydrates. Fennel contains nutrients including vitamin B-3, magnesium, molybdenum, copper, phosphorus, iron, calcium, manganese, vitamin C, folate and potassium.

Fennel Uses

As a health supplement, fennel can help to prevent gas, support digestion and function as an expectorant that can help to relieve minor respiratory problems such as mucus. Fennel also contains anti-inflammatory properties when used externally. The leaves from the fennel plant can facilitate the healing of wounds and burns. The root of the fennel plant is diuretic and can help treat urine infections. Fennel also contains a combination of phytonutrients including the flavonoids rutin, quercitin and kaempferol. Fennel also has antioxidant properties and as a dietary fiber, it can help lower your cholesterol levels.

Fennel Supplements

Health supplement manufacturers offer fennel supplements in powdered form. As a supplement, manufacturers recommend taking 1 to 4 g per day of the powdered fennel supplement. The Food and Drug Administration, however, has not established a recommended dose for fennel powder. There are no known side effects of consuming fennel powder supplements, although you should speak with your doctor prior to using fennel powder if you are attempting to treat a specific medical condition.

The bulb, foliage, and seeds of the fennel plant are widely used in many of the culinary traditions of the world. The small flowers of wild fennel (mistakenly known in America as fennel “pollen” ) are the most potent form of fennel, but also the most expensive.Dried fennel seed is an aromatic, anise-flavoured spice, brown or green in colour when fresh, slowly turning a dull grey as the seed ages. For cooking, green seeds are optimal. The leaves are delicately flavoured and similar in shape to those of dill. The bulb is a crisp vegetable that can be sautéed, stewed, braised, grilled, or eaten raw. They are used for garnishes and to add flavor to salads. They are also added to sauces and served with pudding. The leaves used in soups and fish sauce and sometimes eaten raw as salad.

Fennel seeds are sometimes confused with those of anise, which are similar in taste and appearance, though smaller. Fennel is also used as a flavouring in some natural toothpastes. The seeds are used in cookery and sweet desserts.

Many cultures in India, Pakistan, Afghanistan, Iran and the Middle East use fennel seed in their cookery. It is one of the most important spices in Kashmiri Pandit and Gujarati cooking. It is an essential ingredient of the Assamese/Bengali/Oriya spice mixture panch phoron and in Chinese five-spice powders. In many parts of India and Pakistan, roasted fennel seeds are consumed as mukhwas, an after-meal digestive and breath freshener. Fennel leaves are used as leafy green vegetables either by themselves or mixed with other vegetables, cooked to be served and consumed as part of a meal, in some parts of India. In Syria and Lebanon, it is used to make a special kind of egg omelette (along with onions, and flour) called ijjeh.

Many egg, fish, and other dishes employ fresh or dried fennel leaves. Florence fennel is a key ingredient in some Italian and German salads, often tossed with chicory and avocado, or it can be braised and served as a warm side dish. It may be blanched or marinated, or cooked in risotto.

In Spain the stems of the fennel plant are used in the preparation of pickled eggplants, “berenjenas de Almagro”.

Medicinal uses

Fennel (Foeniculum vulgare) essential oil in clear glass vial

Fennel contains anethole, which can explain some of its medical effects: It, or its polymers, act as phytoestrogens.

The essence of fennel can be used as a safe and effective herbal drug for primary dysmenorrhea, but could have lower potency than mefenamic acid at the current study level.

Intestinal tract

Fennel is widely employed as a carminative, both in humans and in veterinary medicine (e.g., dogs), to treat flatulence by encouraging the expulsion of intestinal gas. Anethole is responsible for the carminative action.

Mrs. Eencher Herbal states:

On account of its carminative properties, fennel is chiefly used medicinally with purgatives to allay their side effects, and for this purpose forms one of the ingredients of the well-known compound liquorice powder. Fennel water has properties similar to those of anise and dill water: mixed with sodium bicarbonate and syrup, these waters constitute the domestic ‘gripe water‘ used to correct the flatulence of infants. Volatile oil of fennel has these properties in concentration. Commercial preparations of fennel  are widely available as alternative treatment for baby colic. Fennel tea, also employed as a carminative, is made by pouring boiling water on a teaspoonful of bruised fennel seeds.

Fennel can be made into a syrup to treat babies with colic (formerly thought to be due to digestive upset), but long-term ingestion of fennel preparations by babies is a known cause of thelarche.

Eyes

In the Indian subcontinent, fennel seeds are also eaten raw, sometimes with some sweetener, as they are said to improve eyesight. Ancient Romans regarded fennel as the herb of sight.Root extracts were often used in tonics to clear cloudy eyes. Extracts of fennel seed have been shown in animal studies to have a potential use in the treatment of glaucoma.

Blood and urine

Fennel may be an effective diuretic and a potential drug for treatment of hypertension.

Breastmilk

There are historical anecdotes that fennel is a galactagogue,improving the milk supply of a breastfeeding mother. This use, although not supported by direct evidence, is sometimes justified by the fact that fennel is a source of phytoestrogens, which promote growth of breast tissue. However, normal lactation does not involve growth of breast tissue. A single case report of fennel tea ingested by a breastfeeding mother resulted in neurotoxicity for the newborn child.

Other uses

Syrup prepared from fennel juice was formerly given for chronic coughs. It is one of the plants which is said to be disliked by fleas, and powdered fennel has the effect of driving away fleas from kennels and stables.

References

  • “Herbs That Work: The Scientific Evidence of Their Healing Powers”; David Armstrong
  • “The Encyclopedia of Herbs: A Comprehensive Reference to Herbs of Flavor and Fragrance”; Arthur O. Tucker and Thomas DeBaggio; 2009
  • “Pocket Guide to Herbal Remedies”; Lane P. Johnson; 2002
  • “Encyclopedia of Natural Medicine”; Michael Murray and Joseph Pizzorno; 1997

seeds

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African medicine-cyclotides as an aid during child birth

African medicine-cyclotides as an aid during child birth

 

Oldenlandia affinis was used by native women in the Zaire as an aid during childbirth. A tea was made of the leaves and imbibed during labour.

Cyclotides are plant-derived peptides of approximately 30 amino acids. They have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. Their unique structural features lead to exceptional stability. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.

David J Craik, University of Queensland, Brisbane, Australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides

Read more

http://www.chemistryviews.org/details/news/5012211/History_of_Cyclotides.html

more info on cyclotides

This is how it was discovered: a physician working in the Democratic Republic of Congo noticed that laboring women were drinking tea made from Oleanda affinis to induce childbirth. Theactive ingredient was the first cyclotide to be discovered. Since then, cyclotides have been shown to be antibiotic, antiviral and insecticidal.

Cyclotide structure.jpg
Figure 1. Structure and sequence of the prototypic cyclotide kalata B1

Cyclotides are small disulfide-rich proteins that have the unusual feature of a cyclic backbone (hence the name cyclo – peptides). They contain six conserved cystine residues that are arranged in a cystine knot topology in which two disulfide bonds and their connecting backbone segments form an embedded ring in the structure that is penetrated by a third disulfide bond, as shown below.

Cyclotides have a range of interesting biological activities including anti-HIV and neurotensin inhibition, anti-microbial activity and insecticidal activity. They are found in a variety of tropical plants from the Rubiaceae and Violaceae families.

The structure of kalata B1 showing the distorted beta-sheet topology and the loop nomenclature enabled by the cyclic backbone.

Cyclotides are small disulfide rich peptides isolated from plants.Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the RubiaceaeViolaceae, and Cucurbitaceae families. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.,

Cyclotides have been reported to have a wide range of biological activities, including anti-HIVinsecticidal, anti-tumour, antifouling, anti-microbialhemolyticneurotensinantagonism, trypsin inhibition, and uterotonic activities. An ability to induceuterine contractions was what prompted the initial discovery of kalata B1.

The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.

The cyclotides have been recognised as a family of novel circular proteins only in the last few years but the discovery of the first member of this family may be traced back to reports of native medicine applications in the early 1970s.

Kalata B1, was discovered because it is an active ingredient in a herbal medicine used by African women to assist childbirth . While on a Red Cross relief effort in the Congo region in the 1960s a Norwegian doctor, Lorents Gran, noted that during labour African women often ingested a tea made from leaves of the plant Oldenlandia affinis because of its uterotonic effects. The active ingredient was determined to be a peptide that was named kalata B1, after the local name for the native medicine. Subsequent in vivo studies in rats confirmed uterotonic activity of the purified peptide but it was not characterised as a macrocyclic peptide until some 20 year later.

The mid-1990�s was a key period in the discovery of macrocyclic peptides, with several independent groups discovering such peptides while screening for various biological activities and our group determining the three dimensional structure of kalata B1 . In the first fortuitous discovery Sch�pke et al., examined Viola arvensis and V. tricolor in a study aimed at the discovery of new saponins. While assaying for the usual hemolytic activity of saponins they discovered a macrocyclic peptide, violapeptide I, with hemolytic activity. At around the same time bio-assay driven screens for anti-HIV and anti-neurotensin activity led to the discovery of the circulins and cyclopsychotride A respectively.

Viola arvensis a cyclotide containing plant. Member of the violaceae family and found in temperate regions of Australia and Europe.

With our report of the three dimensional structure of kalata B1 in 1995 and its sequence homology with the circulins and cyclopsychotride A, we became convinced that macrocyclic peptides might be more common than had earlier been thought and we began searching for other examples. Several other macrocyclic peptides were found in the late 1990s and it became clear that the peptides formed part of a family that we subsequently named the cyclotides.

Several novel cyclotide sequences have been discovered in the last few years , with the known sequences now exceeding 45 and many more currently being characterized in our laboratories. A large proportion of the new cyclotides have been discovered based on their structural properties rather than biological activities. The cyclotides are relatively hydrophobic and can be readily identified from crude plant extracts by their characteristically late elution on RP-HPLC.

The cyclotides described above, all come from plants in the Rubiaceae or Violaceae families but the prevalence of macrocyclic peptides has recently been expanded to include the Cucurbitaceae family. This is based on the discovery of the trypsin inhibitors MCoTI-I and MCoTI-II, 34 residue macrocyclic peptides, from Momordica cochinchinensis . They have no sequence homology to the previously characterized cyclotides, with the exception of the six cysteine residues, but are of a similar size and contain a cystine knot motif (Felizmenio-Quimio, 2001). The MCoTI peptides were originally isolated based on their trypsin inhibitory activity and are homologous to linear cystine knot peptides from the squash family of trypsin inhibitors such as EETI-II and CMTI.

References

Bokesch HR, Pannell LK, Cochran PK, Sowder RC, 2nd, McKee TC and Boyd MR: A novel anti-HIV macrocyclic peptide from Palicourea condensata. J. Nat. Prod. (2001) 64:249-250.

Broussalis AM, Goransson U, Coussio JD, Ferraro G, Martino V and Claeson P: First cyclotide from Hybanthus (Violaceae). Phytochemistry (2001) 58:47-51.

Claeson P, G�ransson U, Johansson S, Luijendijk T and Bohlin L: Fractionation protocol for the isolation of polypeptides from plant biomass. J. Nat. Prod. (1998) 61:77-81.

Craik DJ, Daly NL, Bond T and Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. (1999) 294:1327-1336.

G�ransson U, Luijendijk T, Johansson S, Bohlin L and Claeson P: Seven novel macrocyclic polypeptides from Viola arvensis. J. Nat. Prod. (1999) 62:283-286.

Gran L: Isolation of oxytocic peptides from Oldenlandia affinis by solvent extraction of tetraphenylborate complexes and chromatography on sephadex LH-20. Lloydia (1973a) 36:207-208.

Gran L: On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol. Toxicol. (1973b) 33:400-408.

Gustafson KR, Sowder II RC, Henderson LE, Parsons IC, Kashman Y, Cardellina II JH, McMahon JB, Buckheit Jr. RW, Pannell LK and Boyd MR: Circulins A and B: Novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J. Am. Chem. Soc. (1994) 116:9337-9338.

Hallock YF, Sowder RCI, Pannell LK, Hughes CB, Johnson DG, Gulakowski R, Cardellina JHI and Boyd MR: Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J. Org. Chem.(2000) 65:124-128.

Hernandez JF, Gagnon J, Chiche L, Nguyen TM, Andrieu JP, Heitz A, Trinh Hong T, Pham TT and Le Nguyen D: Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry (2000) 39:5722-5730.

Saether O, Craik DJ, Campbell ID, Sletten K, Juul J and Norman DG: Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry (1995) 34:4147-4158.

Sch�pke T, Hasan Agha MI, Kraft R, Otto A and Hiller K: H�molytisch aktive komponenten aus Viola tricolor L. und Viola arvensis Murray. Sci. Pharm. (1993) 61:145-153.

Witherup KM, Bogusky MJ, Anderson PS, Ramjit H, Ransom RW, Wood T and Sardana M: Cyclopsychotride A, A biologically active, 31-residue cyclic peptide isolated from Psychotria Longipes. J. Nat. Prod. (1994) 57:1619-1625.

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Tribulus terrestris-considered as an energizer and vitalizer in the indigenous system of medicine

Tribulus terrestris-considered as an energizer and vitalizer in the indigenous system of medicine

Tribulus terrestris

Tribulus terrestris is a flowering plant in the family Zygophyllaceae, native to warm temperate and tropical regions of the Old World in southern Europe, southern Asia, throughout Africa, and Australia. It can thrive even in desert climates and poor soil. Like many weedy species, this plant has many common names, including bindiibullheadburra gokharucaltropcat’s headdevil’s eyelashesdevil’s thorndevil’s weedgoatheadpuncturevine, and tackweed.

In traditional Chinese medicine Tribulus terrestris is known under the name bai ji li (白蒺藜). According to Bensky and Clavey, 2004 (Materia medica 3rd edition, pp. 975–976) Tribulus terrestris is ci ji li (刺蒺藜). “Confusion with Astragali complanati Semen (sha yuan zi) originally known as white ji li (白蒺藜 bai ji li), led some writers to attribute tonifying properties to this herb…”

T. terrestris has long been a constituent in tonics in Indian Ayurveda practice, where it is known by its Sanskrit name, “gokshura/ sarrata” It is also used in Unani, another medical system of India.

Apart from its claims for improvement of sexual functions in men, the puncturevine plant (Tribulus terrestris: TT) has long been considered as an energizer and vitalizer in the indigenous system of medicine. Sexual behavior and intracavernous pressure (ICP) measurements were taken in rats to scientifically validate the claim of TT [containing protodioscin (PTN)] as an aphrodisiac.

http://www.ncbi.nlm.nih.gov/pubmed/12804079

Tribulus has chemicals that might increase some hormones in animals. However, it doesn’t appear to increase male hormones (testosterone) in humans.

Chemical control is generally recommended for home control of T. terrestris. There are few pre-emergent herbicides that are effective. Products containing oryzalinbenefin, or trifluralin will provide partial control of germinating seeds. These must be applied prior to germination (late winter to midspring).

After plants have emerged from the soil (postemergent), products containing 2,4-dichlorophenoxyacetic acid (“2,4-D”), glyphosate, anddicamba are effective on T. terrestris. Like most postemergents, they are more effectively maintained when caught small and young. Dicamba and 2,4-D will cause harm to most broad-leaved plants, so the user should take care to avoid over-application. They can be applied to lawns without injuring the desired grass. Glyphosate will kill or injure most plants, so it should only be used as a spot treatment or on solid stands of the weed.

Simmer 500 mg of powered tribulus in organic milk or almond milk, stirring constantly for 5 minutes. You can add 500 mg of standardized maca to enhance the effect. This blend is particularly nourishing and is recommended for both men and women who have lowered libido

Tribulus is a plant that produces fruit covered with spines. Rumor has it that tribulus is also known as puncture vine because the spines are so sharp they can flatten bicycle tires. People use the fruit, leaf, and root as medicine for wide-ranging complaints.

Tribulus is used for kidney problems, including kidney stones, painful urination, a kidney disorder called Bright’s disease, and as a “water pill” (diuretic) to increase urination; for skin disorders, including eczema (atopic dermatitis), psoriasis, andscabies; for male sexual problems, including erectile dysfunction (ED), involuntary release of semen without orgasm (spermatorrhea), and to increase sexual desire; for heart and circulatory system problems, including chest pain, high blood pressure,high cholesterol, and “tired blood” (anemia); for problems with digestion, including colic, intestinal gas (flatulence), constipation, and to expel intestinal parasitic worms; for pain and swelling (inflammation) of the tissue lining the mouth (stomatitis) andsore throat; and for cancer, especially nose tumors.

Women use tribulus to tone muscles before childbirth, to cause an abortion, and to stimulate milk flow.

Some people use tribulus for gonorrhea, liver disease (hepatitis), inflammation, joint pain (rheumatism), leprosy, coughs, headache, dizziness (vertigo), chronic fatiguesyndrome (CFS), and enhancing athletic performance. It is also used for stimulating appetite and as an astringent, tonic, and mood enhancer.

recap

Tribulus terrestris, also known as puncture vine, is a herb that has been used in the traditional medicine of China and India for centuries.

In the mid-1990s, tribulus terrestris became known in North America after Eastern European Olympic athletes said that taking tribulus helped their performance.

The active compounds in tribulus are called steroidal saponins. Two types, called furostanol glycosides and spirostanol glycosides, appear to be involved with the effects of tribulus. These saponins are found primarily in the leaf.

Why Do People Use Tribulus?

Tribulus is most often used for infertility, erectile dysfunction, and low libido. In the last decade, it has become popular to improve sports performance.

Tribulus has been marketed these conditions because research performed in Bulgaria and Russia indicates that tribulus increases levels of the hormones testosterone (by increasing luteinizing hormone), DHEA, and estrogen. The design of these research studies, however, has been questioned.

A more recent study found that four weeks of tribulus supplements (at 10 to 20 milligrams per kg of body weight daily) had no effect on male sex hormones testosterone, androstenedione, or luteinizing hormone compared to people who did not take tribulus.

1) Erectile Dysfunction

Preliminary animal studies found that tribulus heightened sexual behavior and increased intracavernous pressure. This was attributed to increases in testosterone. There haven’t been any well-designed human studies to confirm these early findings.

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Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

 

Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

Scientists are claiming that they have now isolated unusual ingredients in a rare seaweed discovered by fishermen off the coast of Korea that offer incredible health benefits—including the ability to restore blood pressure to normal levels.

The first is Seanol, an extremely rare seaweed extract from Ecklonia Cava that’s proven to be 100 times more powerful than any land-based antioxidant. That’s because it stays working in your body for 12 hours, compared to land-based antioxidants that work for 30 minutes.

“Its secret is its make-up of special polyphenol antioxidants that are a whopping 40% lipid (fat) soluble,” Dr. Lee explains. “Unlike nearly all land-based antioxidants that are water soluble, Seanol’s protective compounds can get into things like the fatty tissues of your brain and penetrate all three layers of your cells, including the outside, the oil-based cell membranes, and your DNA.”

Indeed, Seanol is so powerful, it’s the only FDA-approved Ecklonia Cava marine-algae extract in existence.

The second ingredient is Calamarine, a deep-sea omega-3 discovery that delivers 85% more DHA omega-3s to your heart, brain, joints, and eyes. It’s known to combat everything from fatigue and poor memory, to vision problems, joint pain, mood swings and depression.

http://www.howlifeworks.com/Article.aspx?Cat_URL=health_beauty&AG_URL=Rare_Undersea_Discovery_

Could_Extend_Your_Life_by_10_20_or_30_Years_524&ag_id=1358&wid=DA841499-A4E6-48CA-8C7C-FDD450A22F94&did=4159&cid=1005&si_id=1718

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Ecklonia cava is an edible marine brown alga species found in the ocean off Japan andKorea.

It is used as a herbal remedy in the form of an extract called Seanol, a polyphenolic extract. Another phlorotannin-rich natural agent, Ventol, is also extracted from E. cava.[1]

Phlorotannins, such as fucodiphlorethol G,[2] 7-phloro eckol6,6′-bieckol,[3] eckol8,8′-bieckol8,4″‘-dieckol and phlorofucofuroeckol A can be isolated from Ecklonia cava.[4]

Other components are common sterol derivatives (fucosterolergosterol and cholesterol).[3]

A brownish colored seaweed, Ecklonia Cava, is the base of Seanol trademarked food supplement

 A brownish colored seaweed, Ecklonia Cava
  1.  Kang, K.; Hwang, H. J.; Hong, D. H.; Park, Y.; Kim, S. H.; Lee, B. H.; Shin, H. C. (2004). “Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture”. Research communications in molecular pathology and pharmacology. 115-116: 77–95. PMID 17564307.
  2.  Isolation of a New Phlorotannin, Fucodiphlorethol G, from a Brown Alga Ecklonia cava. Young Min Ham, Jong Seok Baik, Jin Won Hyun and Nam Ho Lee, Bull. Korean Chem. Soc. 2007, Vol. 28, No. 9 1595
  3.  Li, Y.; Qian, Z. J.; Ryu, B.; Lee, S. H.; Kim, M. M.; Kim, S. K. (2009). “Chemical components and its antioxidant properties in vitro: An edible marine brown alga, Ecklonia cava”. Bioorganic & Medicinal Chemistry 17 (5): 1963–1973.doi:10.1016/j.bmc.2009.01.031PMID 19201199.
  4. Ahn, M. J.; Yoon, K. D.; Min, S. Y.; Lee, J. S.; Kim, J. H.; Kim, T. G.; Kim, S. H.; Kim, N. G. et al. (2004). “Inhibition of HIV-1 reverse transcriptase and protease by phlorotannins from the brown alga Ecklonia cava”. Biological & pharmaceutical bulletin 27 (4): 544–547.PMID 15056863.

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Calamarine is new super DHA

One of the myths associated with aging is that your body wears out and there is nothing we can do about it. As we get older, we just have to live with chronic disease and the only way to improve the quality of our health and life is to treat the symptoms.

Overwhelmingly, research suggests that this is simply not true. In fact, the American Journal of Clinical Nutrition and Circulation provide documented evidence that consumption of Omega-3 fatty acids from dietary sources and supplements cut the likelihood of an early death.DHA and EPA not only prevent heart disease and sudden death from a sudden heart attack, they lower the risk…

http://www.marined3.com/Omega.html

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