486

toxin Fimilar to the acidic amino acids, glutamate and aspartate13. Indeed, its lipophilicity renders it more neurotoxic than the non- sulfur amino acids. Cysteine is also toxic to the retina.

GS:-I, on the other hand, is freely soluble in water, reacts only sluggishly with oxygen, and is not neurctoxic. It therefore serves as a soluble, transportable form of cysteine (via the I’-glutamyl cycle).

GSH synthesis largely occurs in the liver. The cysteine from which it is synthesized derives from transsulfuration from methionine rather than from cysteine, for the reasons given above (i.e. the poor ability of the liver to extract cys- teine). Turnover is rapid, the half-life of GSH in the liver being 2-3 h. In excess of 80% of the GSH synthesized is released into the circulation where the kidney promptly extra& the major portion, via the y-glutamyl cycle. Thus, GSH may be an example of the evolutionary trend towards increased molecular complexity in the selection of certain molecular properties of biological advantage and the attenuation of other properties.

But it may not stop there. We are familiar with the concept of

molecules accreting new functions in the course of evolution. Per- haps the loss of function also occurs. It has been suggested that GSH is an evolutionary vestige of a penicillin-like compound christened glutacillin (Fig, 1). The hypothesis is enzymatically feas- ible. The penicillins, along with cephalosporins and cephamycins, are fl-lactam antibiotics produced by microorganisms. Biosynthesis occurs from a tripeptide, amino- adipylcysteinyl-D-valine via cycliz- ation catalysed by isopenicillin N synthase (Fig. 2). There is no reason why glutamylcysteinyl- glycine, or GSH, could not un- dergo a similar enzyme-catalysed cyclization. It was shown in 1949 that GSH inhibited the biosyn- thesis of penicillin (see Ref. 14). At an earlier stage of evolution, penem-type antibiotics such as glutacillin may have been used defensively before further stages of molecular specialization oc- curred. Microorganisms evolved the fI-lactams and a catalog of other antibiotics. Higher species evolved immune systems for defence, relegating GSH to the known and yet-to-be discovered functions it currently has.

B. MAX

Tip5 - December 1989 IVol. 101

References 1 Rosenberg, S. (1971) First Special Reporr

to the U.S. Congress on Alcohol and Health, US Government Printing Office

2 Caddy, G. R. (1983) in Medicinal and Social Aspects of Alcohol Abuse (Tabakoff, B., Sutker, P. 8. and Randall, C. L., eds), pp. l-31, Plenum Press

3 Zobeck, T. S., Grant, B. F., Williams, G. D. and Bertolucci, D. (1988) Trends in Alcohol-Related Fatal Traffic Accidents, United States 19774986, US Public Health Service

4 Abel, E. L., Randall, C. L. and Riley, E. P. (1983) in Medicinal and Social Aspects of Alcohol Abuse (Tabakoff, 8.. Sutker, P. 8. and Randall, C. L., eds), Plenum Press

5 cahalan, D. (1988) Understanding America’s Drinking Problem, Jossey-Bass

6 Clauet, D., Asghar, K. and Brown, R. (1988) Mechanisms of Cocaine Abuse and Toxicity, US Government Printing Office

7 Grinspoon, L. and Bakalar. J. 8. (1976) Cocaine: A Drug and Its Social Evolution, Basic Books

8 Mathias, D. W. (1986) Am. J. Med. 81, 675-678

9 Wiener, D. W., Lockhart, J. T. and Schwartz, R. G. (1986) Am. J. Med. 81, 699-701

10 Galloway, M. P. (1988) Trends P.hmna- col. sci. 9,451-454

11 Kleber, H. D. and Riordan, C. E. (1982) 1. Clin. Psychiatry 43 (Sect. 2). 30-34

12 Kolb, L. and Hirnmelsbach, C. K. (1938) Am. J. Psychiatry 94,759-799

13 Olney, J. W. and Ho, 0. (1970) Nature 227.60%611

14 Spallholz, J. E. (1987) Med. Hypo- theses 23, 25%257

i : ? ..~ - ._ . _. s ._ _.._... .._ ___~_-_-- +...

1 , ..~. ..-. . L. i _” .__... _ ., ._ -..__ _,.._ ,__., __

I : ;

SIGNS new n&s should not add to mnibion

Identification system for stereoisorneric

The recent TiPS article ‘SIGNS: A Stereochemically Informative Generic Name System (Tips, September 1989)’ describes a system which aims to avoid misunderstanding in chemical structures of biologi- caIly active compounds from which stereoisomers can be derived. The system ‘links a few simple prefixes to the established generic names of those drugs that can exist in sfereo- isomeric forms. The prefix in the drug name will identify the fype of stereoisomerism involved and will indicate the single or composite char- acter of the drug”.

Of course, we agree with the authors that scientists in med- icinal chemistry and pharmacology

should be aware of the stereo- chemical identity of biclogically active compounds that they are investigating, and we appreciate their attention. It is well known that two enantiomers may have different biological properties a-xd have to be considered as two different compounds. This differ- ence is not at ail surprising, since two such enantiomers also have different chemical pr,perties when they are in an asymmetric environment, as is frequently en- countered in biological systems (enzymes, receptors, etc.). How- ever, the proposal to add ‘SIGNS prefixes might add a new con- fusion, since the proposed pre-

0 1989, Ekevier Science Publishes Ltd. (UK) Oi65 - 6,47,89,102.00

fixes dexfro and levo for chiral compounds cannot always be established unequivocally, and the cis and truns indications for geometrical isomers have been re- placed by better systems. Re- cently, we have reviewed the existing rules to identify steric isomers, exemplified b biologi- cally active compounds Y .

Opticalisomers In SIGNS the stereochemical

structure of enantiomers is indi- cated by a prefix (dexfro or levo) which refers to the direction of rotation of the plane polarized light by the enantiomers. How- ever, this direction sometimes depends on the experimental con- ditions such as solvent and pH. For this reason, although SIGNS prescribes the measurement of the direction of the rotation in a polar solvent, it does not exclude mis- takes beforehand in the assign- me& of the dexfro and levo prefix. We believe that the indication of the stereochemical structure with the R/S designation, with the

TiPS - Vecember 1989 [Vol. 101

priority established according to the Cahn-Ingold-Prelog se- quence rules (CIP rules)*, is preferable, because it avoids all possible confusion. Moreover, these rules are well established in common chemistry; a separate set of rules for pharmacologists should be avoided.

A more serious problem is en- countered when more than one chiral centre is present in the molecule. With n chiral centres there are theoretically 2” stereo- isomers. SIGNS has only the two prefixes dextro and levo, which is not enough to identify all these stereoisomers. For example, dilevalol (Fig. 1) contains two chiral centres giving rise to a total of four stereoisomers. Two of them will cause dextro- and the other two a levorotation. Thus, a SIGNS terminology of levo-dilevalol would not identify its stereochem- ical structure. The application of the R/S designation is more precise in such cases.

Geometrical isomers The SIGNS system proposes the

use of cis and fruns as prefixes as substitutes for ‘Z’ and ‘E’, respec- tively, to indicate orientations around a double bond. The terms cis and trans are used because they ‘are recognized and understood by a much wider audience than Z and E’l. It would obviously be very unwise to use prefixes that are ‘understood’. when the meaning of these prefixes has been changed. This would further con- fuse rather than clarify the issue. For example, trans-zinoconazole has, according to SIGNS, the structure as indicated in Fig. 1. According to CIP rules, the chloro- thienyl group has a higher pri- ority than the imidazolyhnethyl part, which results in the E desig- nation for this compound.

If, hypothetically, later on homozinoconazole is evaluated, one has to add, according to SIGNS, the prefix cis, since in this molecule, according to CIP rules, the imidazolylmethyl group has a higher priority than the chloro- thienyhnethyl part, which affords the Z-designation for this hom- ologue. It is highly questionable that scientists familiar with cid trans, but not with the E/Z desig- nation will be aware of the cor- rect stereochemical structure. Our advice would be: If one uses EIZ

0

OH CH3

dilevalol

N4

L/ N--C%\ ,&, cl f - a-- \

NdN

‘cl

trans-zinoconazole cis-homozinoconazole

Fg. 1. Slnn2ure.s of dilwal&, trans-zkttwcunazole and cis-homorinoconazole.

rules to identify stereoisomers, then apply E and Z as prefixes in generics as well. It certainly will avoid a lot of misunderstanding.

Finally, SIGNS does not stereo- chemically identify a compound unequivocally if it contains e.g. both a chiral centre and another, differently substituted olefinic double bond. Again, at least two levorotary and two dextrorotary isomers will arise.

Thus, although we agree that stereochemical identification of biologically active compounds is highly desirable, we do not rec- ommend the implemer:tation of SIGNS for this purpose! because with a substantial member of compounds it does not give un- equivocal information (chiral compounds) and may even favour

the development of a lot of mis- understandings (olefinic com- pounds). Instead we propose that the existing rules for stereochem- ical identification are applied, and that publishers require their use in all papers.

I-I. VAN DER GOOT AND H. TIMMERMAN

Department of Phnrmacochemistry, Vrije Universiteit, De Boelelaan 2083, 1081 FJV Amsterdam, Netherlands.

References 1 Simonyi, M., Gal. 1. and Testa, 6. (1989)

Trends Pkarmacol. Sci. 10,349-354 2 van der Goot, H. and Timmerman, H.

(1988) in Stereoselectiuity o,! Pesticides: Biological and Chemical Problems (Ari~ns, E. J., van Rensen, J. J. S. and Welling, A., edsj, pp. 11-38, Elsevier Science Publishers

More education better than new prefixes The article by Simonyi, Gal and Testa (Tips, September 1989)l was thought-provoking and timely. As a medicinal chemist with daily contact with my pharmacological colleagues, I strongly agree with the authors that the pharma- ceutical industry, physicians, and in particular p?annacologists need to be made aware of the stereochemistry of the drugs they are prescribing or using in their research. I cannot, however, support their proposal for the introduction of yet another system to characterize unequivocally the composition of drugs (i.e. dextro, levo, trans, cis, rat, diam and mep).

Fortunately, we have in place the Cahn-Ingold-Prelog conven- tion to indicate absolute configur- ation of chiral molecules. This svstem is used by the Chemical Abstract Service (CAS), United States Adopted Names (USAN) and the LISP Dictionary of Drug Names as well as by IUPAC and other organizations invoived with nomenclature. The problem is not in the lack of a system that desig- nates stereochemistry, but with scientists not using the appro- priate terminology and, even more importantly, failing to understand what the terminology means.

As an example, the GABAA