Stereochemistry and Biologic Activity

The bis-carbazole alkaloids contain previously known monomeric carbazoles as structural subunits. All bis-carbazole alkaloids were isolated only from plants of the genus Murray a, until 1996, when clausenamine-A (203) (see Scheme 2.48) was isolated from the stem bark of C. excavata. The plant M. euchrestifolia is one of the richest sources of carbazole alkaloids. The bis-carbazoles often co-occur with monomeric carbazoles in the root bark, stem bark, and leaves of this plant (3,5-7,158,159). The aspect of atropisomerism for axially chiral, bis-carbazoles was considered only recently. Thus, in many cases it is not clear whether the isolated natural products are racemic or enantiomerically pure. Moreover, little attention has been paid to the relationship between their stereochemistry and biological activity. 

E. J. Ariens, W. Sondijn, P. Timmermans (Eds.) (1983). Stereochemistry and Biological Activity of Drugs. Oxford Blackwell. 

Miyazaki, A. Hotta, T. Marumo, S. Sakai, M., S)Tithesis absolute stereochemistry, and biological activity of optically active cyclodiene insecticides J. Agric. Food Chem. 1978, 26, 975-977. 

Ariens, E. J. Stereoselectivity of bioactive agents general aspects. In Stereochemistry and Biological Activity of Drugs (Ariens, E. J., Soudjin, W., Timmermans, P. B. M. W. M., Eds). Blackwell Scientific Publications Oxford, 1983, pp. 11—32. 

This simple compound 2 was needed by Novartis Pharma Inc. (Basel) for the preparation of a new class of anti-diabetic agents 1. Both enantiomers were needed on a large scale to explore the relationship between stereochemistry and biological activity.1... 

For a report alluding to the biological properties and synthetic importance of optically pure primary amines, see Ariens EJ, Soudijn W, Timmermans PBMWM (eds) (1983) Stereochemistry and biological activity of drugs. Blackwell, Oxford... 

Casy, A.F. (1970) Stereochemistry and biological activity. In Burger, A. (ed.). Medicinal Chemistry, pp. 81-107. Wiley-Interscience, New... 

Soudijn, W. (1983) Advantages and disadvantages in the application of bioactive racemates or specific isomers as drugs. In Aribns, E.J., Soudijn, W. and Timmermans, P.B.M.W.M. (eds). Stereochemistry and Biological Activity of Drugs, pp. 89-102. Blackwell Scientific Publications, Oxford. 

But all work on the stereospecificity of caimabinoid action had been done with (+) THC synthesized according to a procedure published by our group based on commercial a-pinene. And we knew that commercial pinene is not stereochemically pure, and therefore would lead to stere-ochemically impure products. Hence, the lack of stereospecificity could be due to the presence of varying amounts of the active (-) stereoisomer in the presumed pure (+) isomer. So we repeated the synthesis with stereochemically pure (+) a-pinene and tested the (-t) THC produced. It had no (-) THC-like activity, as expected. Then we evaluated the activity in the 11-hydroxy-dimethylheptyl series. As mentioned earlier (-) HU210, is very potent — at least 100 times more than THC. Its enantiomer, (-t) HU211, turned out to be many thousands of times less active than HU210 in a wide series of tests done in collaboration with my friends Billy Martin, Toby Jarbe, and Allyn Hewlett. The stereochemical hurdle was thus overcome. (For a review on the cannabinoid stereochemistry and biological activity, see Mechoulam et al., 1992). 

A microreview on recent advances in the total synthesis of chloro-sulfolipids has been published by Nilewski and Carreira a comprehensive section has been devoted to /-based configuration analysis of these compounds. A review on relationship between stereochemistry and biological activity of fungal phytotoxins has been written by Evidente et al The authors indicate that in many cases NMR spectroscopy, in particular /hh and /hc couplings, was a useful source of information on the relative and/or absolute configuration of these toxins produced by pathogenic fungi. 

Stereochemistry and Biological Activity of Drugs Ariens, E.J. Soudijn, W. Blackwell Cambridge MA, 1983. 

The relationship between its stereochemistry and biological activity was established in 1980. Many aspects of its biological activity, including its endocrine profile, its usefulness as an immuno-modulator, in obstetrics and in gynecology, and in the treatment of pituitary tumors, have been described, along with clinical studies in the treatment Parkinson s disease. 

Chaetomugilins 1-0, new potent cytotoxic metabolites from a marine-fish-derived Chaetomium species. Stereochemistry and biological activities. Tetrahedron, 65, 7580-7586. 

Cardellina, J.H. II and Bamekow, D.E. (1988) Oxidized nakafuran 8, sesquiterpenes from the sponge Dysidea etheria. Structure, stereochemistry and biological activity. J. Org. Chem., 53, 882-884. 

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