Thalidomide, first synthesized in 1953, was widely prescribed for morning sickness from 1957 to 1962, but only outside of the U.S. In 1961 the U.S. Food & Drug Administration was glad it had not given approval, because thalidomide became anathema when it was found to be seriously teratogenic (creating malformation in embryos, from the Greek for "monster") having caused serious birth defects in more than 10,000 babies. Now, a quarter of a century later, it appears that it may be a miracle drug for such diseases as AIDS, leprosy, lupus, and tuberculosis. Within the last year, and over the objection of groups focussed on the risk and seriousness of birth defects, the F.D.A. has approved its use with strict safeguards to protect women who are, or could become pregnant.
Since thalidomide has a stereogenic carbon atom, it exists as two enantiomers. Tests with mice in 1961 suggested that only one enantiomer was teratogenic while the other possessed the therapeutic activity. Unfortunately, subsequent test with rabbits showed that both enantiomers had both activities.
In one sense this is not surprising, because it is likely that the same mode of action is operative in both functions (in many cases it seems to be prevention of angiogenesis, the development of new blood vessels).
In another sense the shared activity seems surprising, because one might expect the enantiomers to interact quite differently (diastereomerically) with the chiral, resolved molecules of nature.
The solution of this second riddle is that the enantiomers interconvert (the compound racemizes) under physiological conditions. Thus the drug is being sold as a racemate.
Thalidomide is very much in the news. A web search will yield hundreds of recent hits. Here are a few representative sites:
Middlebury Thalidomide site of a course on medicinal chemistry for non-scientists with links to other sources.
chiral chromatography Do look at this one which shows a chromatography trace for racemic thalidomide.
The solid stationary phase of the chromatography, a stable enzyme, is chiral and resolved. Therefore the enantiomers cling to it with different tenacity and spend different fractions of their time in the moving solvent, thus migrating at different rates and emerging at different times, i.e. enantiomers are resolved on this chiral column.
The horizontal axis is time to emerge from the column (minutes, increasing to the right), the vertical axis is amount of material (measured by light absorption). The two large peaks are the enantiomers; the smaller peaks are impurities.
What would happen with an achiral column?
What would happen with an achiral column and a resolved chiral solvent?
Lewis A popular account of the role of chirality in drug development. Here's a relevant passage:
Food and Drug Administration (FDA) policy published in 1992 (Chirality, 4:338-340) strongly urges companies to evaluate racemates and enantiomers for new drugs. Even though in many cases a single-enantiomer drug is safer than a racemate, an effective racemate can still be marketed. "If a firm has data supporting the safety and efficacy of a racemate, we'd have to approve it," notes Thomas McGinnis, associate director of pharmaceutical affairs at FDA.
The FDA is interested in chirality for purposes of finding the safest, most effective pharmaceuticals. Lawyers are interested for purposes of extending or sidestepping patents by invoking a different form of matter (say replacing a racemate with a single enantiomer, such a change in technology and patents is called a chiral switch).
An analogous case which has both chemical/biological and patent implications involves different crystal forms of the same chemical substance. Someone like myself, who thinks that non-bonded interactions can be as significant as bonded ones, is very sensitive to the significance of differences in crystal form.
Celgene Announcement by the company that has received FDA approval to market racemic thalidomide. Note that even though their thalidomide is racemic, the page has a link to "pharmaceuticals", where the third paragraph on "Chiral Purity" links to "d-MPH", where one learns that the company is carrying out a chiral switch with ritalin or MPH, which is currently patented and marketed by others as a racemate and prescribed, many would save overprescribed, for attention deficit hyperactivity disorder (ADHD):
Celgene's leading pharmaceutical in the Chiral area is d-methylphenidate hydrochloride, a chirally pure version of Ritalin®. Phase III clinical trials are currently being conducted to determine whether the risk -to-benefit ratio of d-MPH is superior to the non-chirally pure drug that is now commercially available.
A year ago (1998) the corresponding page said
The Company has completed its Phase I/II clinical trial of the chirally pure formulation of d-methylphenidate (d-MPH). This study demonstrated that d-MPH, at one-half the usual doses of dl-MPH, is statistically superior to placebo in improving academic productivity and controlling the behavioral symptoms of children with ADHD. The Study also indicated that d-MPH, at one-half the usual dose of dl-MPH, may have a longer duration of efficacy than dl-MPH. Pivotal studies of d-MPH are planned to initiate in the second half of 1998.
You might enjoy giving this structure its CIP stereochemical descriptor (the carbon next to the CO2CH3 group is numbered 2, C6H5 is a phenyl ring) and naming the configuration of its stereoisomers (how many of them are there?).