QSAR Studies of Copper Azamacrocycles and Thiosemicarbazones:MM3 Parameter Development and Prediction of Biological Properties

摘要

Genetic algorithms (GA) were used to develop specific copper metal-ligand force field parameters for the MM3 force field,from a combination of crystallographic structures and ab initio calculations.These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters for the AMBER force field.The MM3 parameters were then used to develop several quantitative structure-activity relationship (QSAR) models.A successful QSAR for predicting the lipophilicity (log P_(ow)) of several classes of Cu(II)-chelating ligands was built using a training set of 32 Cu(II) radiometal complexes and 6 simple molecular descriptors.The QSAR exhibited a correlation between the predicted and experimental log P_(ow) with an r~2 = 0.95,q~2 = 0.92.When applied to an external test set of 11 Cu(II) complexes,the QSAR preformed with great accuracy;r~2 = 0.93 and a q~2 = 0.91 utilizing a leave-one-out cross-validation analysis.Additional QSAR models were developed to predict the biodistribution of a smaller set of Cu(II) bis(thiosemicarbazone) complexes.