Structure-activity relationship between the 3D distribution of the electrophilicity of sugar derivatives and their cytotoxic and antiviral properties

Abstract

The cytotoxic activities of a series of sugar derivatives bearing electrophilic groups (1-cyanovinyl, 4-cyanochromen-2-yl and 3-nitrochromen-2-yl) have been correlated with their electrophilic properties. To this end, an electrophilic index was defined as an isovalue surface where the interaction energy with an incoming model nucleophile (H-) was equal to a predefined value. This index, calculated from extended Hückel wave functions, allows one to quantify the electrophilic character of the substrates and to describe its spatial localization within the molecular volume (at Michael acceptor sites or on other parts of the molecules). Only sugars for which Michael acceptor reactivity was predicted were retained, and they were subdivided into two groups: those showing antiviral activity against a retrovirus and those devoid of such activity. Under these conditions, good correlations between cytotoxic activity and electrophilic reactivity--positive for the first group, negative for the second--were found. In addition, the ratio electrophilicity/sum of the absolute value of the dipole plus its projection along the principal axis of inertia, Z, of the molecule allows one to predict to which of these groups a sugar derivative belongs.

Synthesis and in Vitro Cytotoxic and Antiviral Activities of 1-(2,5,6-Trideoxy-6-Halogenohept-5-Enofuranurononitrile)thymine and Derivatives

“…The 1-cyanovinyl group, a soft electrophile, fixed onto blocked sugars or ribonucleosides has been shown to bear cytotoxic and=or antiviral properties 1,2 somewhat dependent on its electrophilicity 3 . We describe here the fixation of a positional isomer of this group, a 2-cyanovinyl, and all its common 2-halogeno derivatives on the 5 0 position of a more biologically promising host molecule, the 2 0 -deoxythymidine.…”