Articles by: Quintus

A Bottle a Day keeps the Aging Away

Following on from the tea party where polyphenols reared their (ugly) heads a “highlight” has appeared in Angewandte Chemie English edition1, 2 pointing out the benefits of red wine, i.e. resveratrol. This is a well-known molecule, which has been at the centre of some controversy of late. Resveratrol is chemically trans3,5,4’-trihydroxystilbene:

This compound can be found in many types of fruits and nuts berries AND grapes. Its concentration in red wines varies between 0.1 and 14 mg/L whereby the 3-glycosate achieves levels of 30 mg/L. Frequently associated with this compound is the “French Paradox”, not that the French are a paradox themselves, but that apparently, in spite of consuming large amounts of saturated fats and barrels of red wine, the incidence of heart disease is lower that one might well expect it to be3. Resveratrol has a plethora of biological activities associated with it:

  1. It was originally noticed for its inhibitory effects against the oxidation of lipoproteins, the low-density variety being present at the onset of atherosclerosis4.
  2. Lowering lipid levels5.
  3. Moderate anti-oxidant properties.
  4. Protective for cancer, inhibiting cellular events associated with tumour initiation, promotion and progression6.
  5. It apparently also has a positive effect in diabetes and Alzheimer’s disease.
  6. It is able to activate sirtuin, thus mimicking calorie restriction and hence slowing the aging process.
  7. It also prevents phosphodiesterases from degrading cyclic AMP, also a mechanism of calorie restriction and hence age slowing.

What a list, I wonder what remains to be discovered?

Derek Lowe, at In the Pipeline  has commented extensively on this molecule and I recommend you all to have a read at the following plus the comments from his learned readership;

  1. The Latest Sirtuin Controversy
  2. Resveratrol in Humans: Results of a Controlled Trial
  3. The Sirtuin saga
  4. A resveratrol Research Scandal. Oh, joy
  5. Defending Das’ Resveratrol Research. Oh, Come On.
  6. Would I take resveratrol? Would You?

More about the sirtuins can be found on this page. In detail sirtuin1 information can be found here.

I do not profess to be conversant with all the details surrounding the apparent controversy concerning this compound and its biology. However, there is also big money at stake. GlaxoSmithKline acquired Sirtis, a company founded to discover and develop small molecules with at least some of the seven biological properties listed above. So presumably they are carrying out extensive medicinal chemistry on resveratrol. This won’t be an easy task to pick out one given the multitude of activities associated with this system, perhaps they can bundle 5,6 & 7 together. That is, of course, if there is any money left after paying the rather large fine recently dished out by the US Government. But, there is always the chance of off label indications being discovered!

Well, I shall certainly extend my red wine cellar but there won’t be many bottles in it, as I must take my daily dose of resveratrol by the bottle, especially at my age. Not to mention imbibing in tons of vitamin c and gallons of green tea. So when I drop dead after taking that lot no doubt I shall be considered as “toxic waste” and be treated accordingly.

References:

  1. Quideau, S., Angew Chem Int Ed Engl. 2012, 51(28), 6824-6826.
  2. Quideau, S., Angew Chem Int Ed Engl. 2011, 50(3), 586-621.
  3. S. Renaud, M. de Lorgeril, Lancet 1992, 339, 1523 – 1526.
  4. E. Frankel, A. Waterhouse, J. Kinsella, Lancet 1993, 341, 1103 – 1104.
  5. H. Arichi, Y. Kimura, H. Okuda, K. Baba, M. Kozawa, S. Arichi, Chem. Pharm. Bull. 1982, 30, 1766 – 1770
  6. M. Jang, L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. W. Becheer, H. H. S. Fong, N. R. Farnsworth, A. D. King- horn, R. G. Mehta, R. C. Moon, J. M. Pezzuto, Science 1997, 275, 218 – 220

Now we can’t drink tea!

If you’re a man and you live in Scotland do not drink tea. According to a BBC report  >7 cups a day give you a >50% greater chance of developing prostrate cancer than “normal” tea drinkers. This was the result of a  study over 37 years involving 6000 volunteers aged between 21 & 75 years of age. I’m surprised they didn’t choose whisky and/or beer (they have probably been checked at some point in distant past). This is in direct contrast to a National Cancer Institute report which suggests the opposite, at least for green tea.

What’s next I wonder, coffee is already on the black list, as well as fatty foods smoking, no doubt sex will also rear it’s ugly head in the list of cancer producing agents, water is also dangerous, fish swim in it and you can drown as well.

Wiki tells us the exact opposite to the results reported by the Glasgow study. Tea is actually beneficial for you in all sorts of ways.

So what’s in tea that makes it so harmful or so good for you? Well there is theanine and caffeine, making up about 3% of its dry weight up to 90mg per cup, depending upon the tea. Theanine moves across the blood brain barrier (quite distant from the prostrate) and has a synergistic effect with caffeine, high doses even providing a neuroprotective effect. Caffeine is a stimulant and the author of the Wiki page suggests that it may even have moderately protective effect against certain cancers.

 

There are also things like theobromine (or should it be teaobromine) and theophylline. So those compounds are  probably not the cause of this higher prostrate cancer risk.

What else?

Up to 30% of the dry weight of tea are the catechins. These look like a possible candidates! Some present in green tea are shown below.

 

Just look at all those nasty phenols, they may even have antioxidant properties, but as carcinogens, well,  I think they are not very high on the list.

The tea plant apparently has the capacity to absorb lots of the pollutants we pump out every day, e.g. fluoride and aluminum, the latter  can be present up to 30,000ppm by dry weight! Exactly what the form of the fluoride and aluminum is I don’t know, presumably sodium fluoride, perhaps someone can enlighten me as to the aluminum source.

So everyone, what shall we drink now? How about red wine, with all that reservatrol it must be good for you perhaps the chances of developing cancers will be reduced. It’s like everything we do (apart from working and paying tax), taken in moderation it is very enjoyable, but taken in excess, well I guess we have all suffered a hangover at some time.

Enjoy your tea breaks.

 

The Organic Chemists Dream

Now here is something, the simultaneous formation of 96 bonds in a one-pot reaction!! Yes, 96 bonds at one go.

This feat was recently reported in Angewandte Chemie DOI: 10.1002/anie.201202050 , entitled Integrative Self-Sorting Synthesis of a Fe8Pt6L24 Cubic Cage, but I do not profess to understand it.

This would be great for organic chemists. Imagine throwing together carbon, hydrogen, nitrogen, oxygen and a bit of sulphur and a few other trace elements and shaking (not stirring) and out pops a blockbuster drug or a new life form!

Here is what they produced.

 

Sandwiches and other tasty things.

Sandwiches have a long and colourful tradition, said to have been invented by the Earl of Sandwich in the 18th century who apparently ordered his servant to bring him some meat tucked between two pieces of bread. So thus the delicacy was born. I can vouch for the town of Sandwich, in Kent, England, which is a beautiful place, full of old buildings and more importantly pubs selling good beer and guess what? Sandwiches.

Pfizer had a facility there, but in their infinite wisdom they recently closed it. Just up the road was a fireworks factory, lots of little huts dispersed about a rather large field, presumable to avoid explosion of rotten sandwiches. Even further up the road there used to be a hovercraft terminal, which, for a  large fee would transport you and your car over the English Channel to France. That was in the days before the channel tunnel.

To a chemist the word sandwich has another connotation, sandwich compounds in which a metal atom sits between two rings, usually cyclopentadienes. Recently a review appeared describing the discovery, structural elucidation and uses of these interesting compounds (1). I was amazed to read that R.B. Woodward also had his fingers in the pie, or rather sandwich, which I suppose is not too surprising.

Some 60 years ago reports appeared, in Nature and the Journal of the Chemical Society (2,3), describing attempts to prepare fulvalene by oxidising cyclopentadienylmagnesium bromide with FeCl3. They obtained yellow crystals, always nice to see, but they turned out not to be the correct compound, elemental analysis gave the formula FeC10H10 . This compound was soluble in conc. H2SO4 , without decomposition. You can’t say that about modern day sandwiches, except for the ones the railways serve on their roving buffet wagons.

As is the case, and there many examples of it, another group isolated the same compound from an unrelated series of experiments.So what was the structure of this new compound? The big names became involved in solving the puzzle, proposals came from Ernst Otto Fischer (right hand structure), R.B. Woodward, G, Wilkinson (left hand structure).

Their proposals were finally vindicated by X-ray crystallography.

Woodward published his thoughts (4, 5) and proposed the name “Ferrocene” which became generally accepted. Thus compounds of the type M(C5H5)2  became known as metallocenes. Wilkinson and others coined the name “Sandwich compounds”, which also became universally accepted. As an interesting aside; apparently the JACS editor who had the job of refereeing the Woodward communication wrote to him and Wilkinson suggesting that they may have been imbibing in some illegal substances!

The research into these compounds proceeded at a furious pace between 1952 and 1954 and it was observed that the “all’s fair in love and war” policy was strictly adhered to by both the Fisher and the Wilkinson groups. Nevertheless this work produced a plethora of remarkable compounds and I will leave it to the reader to investigate the original literature so well documented in this Angewandte Chemie essay (1).
In 1973 Fischer and Wilkinson were awarded the Nobel Prize for their sandwich work and it’s refinement. Not surprisingly there were those not quite so thrilled with this decision, even going as far as to suggest that a “grave injustice” had been committed. The Nobel Committee reacted appropriately to this correspondence.
Sandwiches have even made their way into the realms of medicinal chemistry. Very recently Salmon etal (6) described Metallocene-Based Inhibitors of Cancer-Associated Carbonic Anhydrase Enzymes IX and XII in the Journal of Medicinal Chemistry. They investigated 20 different sandwiches “comprising of extensive structural diversity” and evaluated their efficacy an inhibitors of carbonic anhydrase. The most potent compound, a sulfonamide, is reproduced here.                                                                                                                          

Derek Lowe at “In the Pipeline” commented on this paper and his contributors added more and the reader is recommended to peek in there (7)!

I myself dabbled in this chemistry, well I cheated and bought my ferrocene derivative. But all the chemistry planned worked and I even obtained an x-ray structure, which I think looks wonderful!

 

 

Well there it is, my first contribution of, I hope, many to Chemistry Blog. I hope you all enjoyed it. Any comments are welcome, except negative ones which will get a mouldy sandwich thrown at them. I recommend everyone to have a read at reference 1, if you can, it’s behind a paywall, as to be expected. We need open access journals.

References

  1. Helmut Werner, Angewandte Cheme International Edition English, 9th May, 2012, DOI: 10.1002/anie.201201598.
  2. T. J. Kealy, P. L. Pauson, Nature 1951, 168, 1039 – 1040.
  3. S. A. Miller, J. A. Tebboth, J. F. Tremaine, J. Chem. Soc. 1952, 632 – 635.
  4. G. Wilkinson, M. Rosenblum, M. C. Whiting, R. B. Woodward, J. Am. Chem. Soc. 1952, 74,2125 – 2126.
  5. R. B. Woodward, M. Rosenblum, M. C. Whiting, J. Am. Chem. Soc. 1952, 74, 3458 – 3459.
  6. Adam J. Salmon, Michael L. Williams, Quoc K. Wu, Julia Morizzi, Daniel Gregg, Susan A.Charman, Daniela Vullo, Claudiu T. Supuran, and Sally-Ann Poulsen; J. Med. Chem.,Publication Date (Web): April 27, 2012 (Article) DOI: 10.1021/jm300427m
  7. http://pipeline.corante.com/archives/2012/05/23/how_come.php
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