SAR of Cu (II) thiosemicarbazone complexes as hypoxic imaging agents: MM3 analysis and prediction of biologic properties.

Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r(2) = 0.95 and q(2) = 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: Log P = {3.01698 (+/-0.0590)} - LUMO {0.1248 (+/-0.068)} + MR {0.3219 (+/-0.086)} n = 21 |r| = 0.972 s = 0.188 F = 98.102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds.