Alfred Burger

Isosterism and bioisosterism in drug design.

In every scientific undertaking that is to break new ground, one has to have a goal, a working hypothesis, or a leading idea or fact. This will encourage research and help in the pursuit of a worth-while objective, be it the enrichment of knowledge or the elaboration of a practical purpose. A medicinal scientist who hopes to find a new biologically active drug will have to be guided by such considerations.

Mechanism-based inhibitors of monoamine oxidase.

Through the study of mechanism-based inhibitors, it has been shown that the two-electron oxidation of biogenic amines carried out by the flavin moiety of monoamine oxidase occurs by stepwise electron transfer. This is illustrated by cyclopropylamine-based inhibitors. Mechanisms of propargylamine- and hydrazine-type inhibitors have also been clarified.

Relationships of chemical structure and biological activity in drug design

The desire to study relationships of chemical structure and biochemical or biological activijy is based on the age-old hope of mankind to understand the connection between different phases of Nature and the role living organisms play in ii. Medicinal chemists need this knowledge for predictmg such relationships and thereby devisimg guidelines for the design of drugs and other biologically active substances. IJnfortunately, there are no absolute ground rules in this endeavour. As in all other scientific measurements, we require some primary standards to which other observations can be referred. Such primary pharma,cological standards are the ‘lead’ compounds in drug design, They are found by screening and provide the parameters for ph(armacoIogical tc%t methods. Random screening has been superseded larpely by selecting chemicah, usually of carefully planned structure, which shotuld be active in a given test sy.stem. After a ‘tead’ has been found, molecular moditication takes over. it offers ahe hope that suitable structural variation may increase the therapeutic usefulness of 5: ‘lead’ compound by widening ‘:tde r,uio of desirable actions and potency to the inevitable toxicity syndrome ,that al) materials will present at higher doses.

Cyclopropane Compounds of Biological Interest

The cyclopropane ring is a relative newcomer to be recognized in natural products of biological interest, and to be applied synthetically to prospective biologically active compounds. The syntheses of biologically active cyclopropane derivatives have been studied only during the last 25 years. Ideas concerning the biosynthesis of naturally occurring cyclopropane compounds have been formulated still more recently. Although cyclopropane itself has been used as a general anesthetic in the clinic since 1930, more than 30 years passed before the first cyclopropane derivative, trans-2-phenylcyclopropylamine, became available in medicine. A number of cyclopropane fatty acids had turned up as constituents of certain lipids, but their origin and function did not become understood until much later. These slow developments contrast with the high level of activity in the purely chemical study of cyclopropane and its derivatives. Here the formation of such compounds from olefins or by photochemical reactions, and their ability to rearrange, have had high priority among organic chemists. Kinetic, theoretical, orbital-overlap, and bond-strain studies have also received considerably more attention than medicinal and biological investigations.

3, 4-Dihydroxyphenylalanine and Related Compounds

This review covers essentially derivatives of β-phenyl-α-alanine which contain two phenolic hydroxyl groups, and some of their analogs and derivatives. They comprise β-(3, 4-dihydroxyphenyl)-α-alanine (dopa) and the few known ethers and ring substituted derivatives of this amino acid, as well as derivatives of dopa substituted in the alanine group. Among these compounds are β-(3, 4-dihydroxyphenyl)serine (3, 4-dops), α-methyldopa, and some of their derivatives. Position isomers containing two phenolic hydroxyl groups in positions other than 3 and 4 have been included. The chemistry, biochemistry and pharmacology of these compounds are the subject of sections of this review.

The State of Medicinal Science

Medicinal science involves the study of pharmaca, especially of chemicals used in medicine as therapeutic and occasionally as prophylactic agents. It is based on combinations of experimental biology and chemistry and physics applied to the understanding of pathologies and restoring normal conditions in animal cells and tissues. The widest areas contributing to medicinal science are medicinal chemistry, biochemistry and pathology applied to metabolic aberrations, pharmacology, microbiology and virology, endocrinology and immunology. Many medical specialties funnel information into medicinal science and vice versa where pharmacotherapeutic treatment is involved. It would be a great advantage if unified concepts could be found to tie all these activities together. In physics and chemistry, the trend toward such generalizations is making progress. Biology and behavioral sciences are approaching the stage at which many of their phenomena are becoming classifiable as chemical and physical manifestations. But unified explanations in biology run into difficulties through refined visual observations and instrumental measurements. As we advance toward visualization of macromolecules by electron microscopy, X-ray diffractometry and other spectroscopic methods, we witness a centrifugal expansion of what had been thought to be ultimate biological entities only a few years ago. Where ‘animate’ matter and macromolecules meet we recognize the growing importance of molecular aggregation and polymerization.