Conformation states of nitrogen-containing heterocyclic compounds and their biological significance

Abstract

The unusual wealth of chemical transformations in the cell leads to the synthesis of compounds with a broad spectrum of properties and a great diversity of the structures. The use of physicochemical and biochemical methods in studying these compounds makes it possible to study the fine details of their structure, examine the problems of the interrelationshi p between different types of natural compounds, and establish the rules of their chemical behavior. A major problem at the present time is a study of the chemistry of natural and synthetic compounds in intimate association with their physiological function at the molecular, subcell and cell levels in order to know the physicochemical essence of life processes and their regulation in the organism. Instead of the synthesis and testing of numerous series of compounds it is necessary to make a more detailed study of the mechanism of the involvement of a given class of compounds in the biochemical processes that proceed in a definite locus of the cell, and to establish the structural traits of the reaction forms and the conformation states of the molecules that determine their specificity and functional preferences. The principle of a topochemical conformity [1] proved useful when searching for myorelaxants [2, 3], cholinolytics [4, 5], antibiotics [I], herbicides [6] and anesthetics [7]. Information on the mechanism of the action of compounds at the molecular level led to a more directed productive search. At the same time, the development of the conformational analysis of sterically labile physiologically active natural compounds [8-11], including our studies of the alkaloids belonging to the bipyridine [10, 12], quinolizidine [9, Ii] and tropane [13] groups, and also their derivatives, show that the principle of a topoehemical conformity must be expanded to take into account the possibility of the induced eonformational transformations of the substrates under the influence of reaction with the molecules that carry out a given biological proeess. The complex problem arises of establishing not only the preferred conformation of the compo~mds, but also the forms into which they are reversibly transformed. The concentrations of these conformers are frequently small, but specifically they can correspond to the configuration of the active centers of enzyme systems. This situation differs from the principle of the Koshland induced conformity [14] and is the consequence of the Hammett-Curtin kinetic criterion [15, 16]. Consequently, a study of the paths of the conformational transitions and the spatial structures that are found in equilibrium with the preferred conformations assumes paramount significance in elucidating the mechansim of the functioning of physiologically active compounds.