| Camptothecin (CPT), exhibits cytotoxic activitya as an antitumor drug. CPT with inhibition to ubiquitous enzyme topoisomerase I (ToPo I), composes CPT-ToPo I-DNA complex, prevents DNA religation, results in death of tumor. The antitumor activity is only appeared by 20S-CPTs, when 208-configuration is changed into 20R-configuration or E ring is broken, CPTs' antitumor activity is sharply reduced or lost. Report to study 20S-CPTs' QSAR is seldom published; till now, there is no research can find the reasons: Why CPTs with 20S-configuration have higher antitumor activity than those with 20R-configuration? Why CPTs with break E ring with less antitumor activity?In order to find QSAR of 20S-CPTs, in order to discover the above reasons, 80 compounds of 20S-CPTs, 20R-CPTs, E ring break CPTs have been calculated by molecular mechanics and quantum chemistry methods AMI. The structure-activity relationship and the components of orbits have been discussed; results consistent with experiments are obtained:(1) Ring A,B,C,D are in one plane?n MO is necessary for the stabilization of CPTs.(2) The plots of frontier molecular orbit of 20S-CPTs indicate that the area of ring D and the C<23 binding to ring D maybe the negative electronic active center with influence on acceptor, the percent of ring D and 023 of 20S-CPT HOMO orbit reduces when configuration changed from S to R or when ring E breaks, it indicates that less percent in HOMO orbit of the negative electronic active center results in less antitumor activity.(3) 20S-CPTs with less î–’UMO than 20R-CPTs and ring E break CPTs, it demonstrates that less î–’UMO benefits to higher antitumor activity.(4) A QSAR is obtained; logP values of 20S-CPTs and activity is a parabola model, logP has important effect to antitumor activity, the net charge of ring D, QC2Q, QO23 and DIPO are also important factors influencing 20S-CPTs antitumor activity.The result is with significant value to drugs synthesize, filter and drugs action mechanism. |
PDF Full Text Request