Thursday 9 August 2007

Medicine-Chiral drugs

Business India, February 13-26, 1995

Molecular Jekyll and Hyde

Mirror images of the same molecule could have widely differing effects on living organisms

Shivanand Kanavi

Can the mirror image of an object differ from the original? Common sense would suggest not. But, sur­prisingly, the mirror image of a molecule may not only be different but even have opposite effects on the human body. The most dramatic example of this duality was thalidomide. Thalidomide-R is a hypnotic drug, introduced in the 1960s, which suppresses signals from the brain, giving rise to nausea and morning sick­ness in pregnant women. However, when its use resulted in the birth of a large num­ber of severely deformed children, the world was shocked. It was discovered later that the mirror image of thalido­mide-R, called thalidomide-S, was pre­sent in the dosage in equal quantities and was the culprit that led to these terato­genic, or foetal, effects.

'Chirality' , or the different behaviour of 'enantiomers' (molecular mirror images) was, in fact, discovered way back in 1848 by Louis Pasteur. He found that tartaric acid exists in two forms - which were later found to be mirror images of each other. While one form of tartaric acid polarised incident light in one direc­tion, the other did it in the opposite direc­tion. However, chirality remained little more than a curiosity till the thalidomide tragedy struck.

The last 30 years of research in chiral­ity has yielded many such startling exam­ples. But what is the difference due to? "Nature is chiral," explains A.V. Rama­rao, director of the Indian Institute of Chemical Technology, Hyderabad, and a world authority in chiral chemistry. "Amino acids, sugars, enzymes, peptides and carbohydrates found in the human body are chiral. In fact, the complexity of chirality seems to increase in plants and animals that are higher in the evolution­ary scale. Higher chirality 'shows greater selectivity in reactions arid higher specialisation in the functions of different molecules. So participants in biochemical reactions like drugs, pesticides, per­fumes, flavours, etc., have to be of the right chirality. Only the right key can open the lock. A wrong key at best might not open any lock, as in the case of non­toxic and non-therapeutic ibuprofen-R, or at worst might even open a Pandora's box as in the case of thalidomide-S," he points out.

Even if a mirror image were non­toxic, as in the case of ibuprofen, the fact that the body has to metabolise 50 per cent of the dosage given without any use­ful effect is tanta­mount to polluting the human system. This could become particularly serious in old age when pain­killers are increas­ingly used even as the body's metabolism weakens.

Nearly half the drugs that are com­mercially available in the market have chi­ral centres and hence exist as paired enan­tiomers. Many of the pure enantiomers sold today are derived from plants or micro-organisms. Only about 10 per cent of the synthetic drugs are sold as chi­ral molecules while the rest are marketed as mixtures of both enantiomers called 'racemates'. But the situation is fast changing with drug regu­latory authorities in the US, Switzerland and Japan insisting that pharmaceutical companies start introducing new drugs as chirally pure molecules, although no defi­nite deadline has been set for the same. It is expected that nearly 50 per cent of the new drugs in the next ten years will be introduced in a chirally pure form. Among the top-selling drugs today, cap­topril, enalapril, diltiazem, cefaclor and naproxen are chiral.

So the race is on to develop chiral technology for both old and new drugs. While various methods are available for chiral synthesis, the tricky part is to develop cost-effective methods. Ramarao ­believes that if we invest time and money ­in chiral chemistry now in India, we will soon be able to develop the necessary technology and join a select band. His work in the case of a new wonder drug, the immunosuppressant FK-506, has become internationally known – IICT is the only group that has been able to synthesise FK-506 outside the US.

It all began with an innocuous news item that said that a prominent politician from Tamil Nadu who had undergone an organ transplant in the US needed drugs worth Rs50,000 a year to keep him alive. The expenditure raised a storm in the Tamil Nadu assembly. Ramarao found it interesting enough to investigate what the particular drug was. It turned out to be a cyclosporin which is used as a post-operative drug. Following an organ transplant, the body normally tends to reject the new organ as the immune system is programmed to treat it as a foreign body and fight it. Cyclosporins suppress this immune sys­tem, thereby making the body co-exist with the new organ. But if the immune system as a whole is suppressed, the body becomes prone to attack by other serious infections. Thus, cyclosporin levels have to be closely monitored and the drug needs to be taken continuously.

A Japanese company introduced FK 506 as the next generation immunosuppressant which has a very high selectivity. In fact, without suppressing the immune system indiscriminately it makes the body accept the new organ. The drug has performed wonders. Recently, a patient at the Pittsburgh med­ical school needed a liver transplant but, as a human donor was not available and the patient was sure to die, the doctors transplanted a baboon's liver. They then treated him with FK-506; quite incredi­bly, the patient survived for 30 days!

FK-506 has 14 chiral centres in its structure. During chemical synthesis, one can go wrong at any of the 14 points. By contrast, thalidomide has only one chiral centre. That is why Ramarao and nCT, Hyder­abad, created waves in the world of organic synthesis when they suc­ceeded with FK-506. But, as Ramarao admits, "This is still basic research. We are far away from developing a commercially viable process for FK-506." However, BCT'S chiral technology for anti­hypertensive beta blockers, etc, has already been transferred to industry.

Chiral synthesis has three basic approaches. The first is resolving a racemic mixture of two crystals with different melting points by preferential crystallisation. The anti-typhoid chloramphenicol is separated thus. This is used widely in the industry but hardly 20 per cent of racemates appear in this form of mechanical mixture or 'conglomerates'. In many cases the enantiomers can be resolved by making the mixture react with a pure organic acid or a base of the right chirality. The racemates separate to form two diasteromeric salts, ie salts with two chiral centres where one chiral centre is identical but the other one is dif­ferent. The popular anti- TB drug etham­butol, phenyl glycine and the cardiovascular drug diltiazem are sepa­rated this way. These methods of resolution are industrially very widely used.

The second method is called asymmetric synthesis. Here one makes use of the fact that most natural products such as amino acids, carbohydrates, etc, are chiral. They are used as starting materials and as molecular templates to synthesise the required chirally pure compound. Another popular method is to use chiral catalysts, called 'chemzymes' by Nobel Laureate E.J. Corey. A large number of drugs like Vitamin C, semi-synthetic penicillins, cephalosporins, timolol, propranolol, diltiazem, thienamycin, ampicillin, dopa, naproxen, etc, are man­ufactured this way, using asymmetric synthesis.

The third method which is also creat­ing a lot of interest is enzymatic transfor­mations. Enzymes are naturally occurring chiral catalysts and are highly selective. The stages in this method involve fermen­tation to produce the required enzyme, enzymatic transformation reaction, sepa­ration of the enzyme without losing its bio-catalytic activity, and separation and purification of the product. One has to find economically viable conversions at all stages. Enzymes can be used to sepa­rate racemic mixtures as well as for bio­asymmetric synthesis.

Chiral technology will be important enough to attract funds for development in India too. Abbot Laboratories of the US, Lupin Laboratories and Cipla are funding research in this field at IICT. Ramarao is convinced that India, which has already shown its strength in organic synthesis both in academia and industry, can get into the big league in chiral tech­nology if sufficient investment is made in the field now.


Sales of chirally pure drugs crossed $35 billion in 1993


Class of Drugs 1998 world wide Sales ($ billion)

Cardiovascular 11.3
Antibiotics 10.8
Hormones 4.5
Neurological 2.0
Anti-inflammatory 1.5
Anti-cancer 1.0
Others 4.5


Total 35.6


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