Investigation of a Binding Model for Anti-Cancer Cyclohexadienones by Computational Chemistry and Crystallography

Abstract

A series of aryl-substituted quinols have shown good anti-cancer activity, and the crystal structure of the benzothiazole-substituted compound had recently been determined in the Aston University laboratory. The geometry of the reactive cyclohexadienone ring in this structure and related molecules in the Cambridge Structural Database has been surveyed. The allowable steric relationship between this ring and the benzothiazole ring has been investigated by molecular modelling. Thioredoxin is believed to be the biological target, with two of its cysteine thiol groups attacking the double bonds of the quinol ring. The geometry and stability of model adducts in which thiols bind to the cyclohexadienone ring in the possible alternative orientations have been compared. The geometry and thermodynamics of thioredoxin binding have been modeled. The previously determined crystal structure of a related quinol in which the aryl substituent is an indole derivative had been seriously affected by twinning. A higher-quality specimen crystal has been found and used to collect twice the required unique set of data, enabling reliable comparison of the two independent molecules in the asymmetric unit to be made. As a path-finding project an improved specimen crystal was found and used for the amidrazone DLR944. This structure also has two independent molecules in the asymmetric unit, and a previous data set had given unrealistic displacement parameters for a t-butyl group. The new data set gives a more credible picture.