20-(S)-camptothecin analogues as DNA topoisomerase I inhibitors: a QSAR study

The interest in the application of the quantitative structure-activity relationships (QSAR) has steadily increased in recent decades because it has repeatedly proven itself to be a low-cost, high-return investment. Potential use of QSAR models for screening of chemical databases or virtual libraries before their synthesis appears equally attractive to chemical manufacturers, pharmaceutical companies, and government agencies. We hope it may also be useful in the design and development of new camptothecin derivatives as DNA topoisomerase I (topo I) inhibitors. In this paper, two series of camptothecin derivatives were undertaken to correlate DNA topo I inhibition with their hydrophobic and steric properties, to understand their chemical-biological interactions. The resulting QSAR have shown that the inhibitory activity of camptothecin analogues 4 toward DNA topo I is mainly dependent on their hydrophobic and steric descriptors, whereas the same activity of 10,11-methylenedioxy- camptothecin analogues 5 is largely dependent on their hydrophobicity at position-7. Using internal [cross-validation, quality factor (Q), Fischer statistics (F), and Y-randomization tests] and external validation tests both of these QSAR models have been validated. Both series of these camptothecin derivatives are also filtered by Lipinski's rule of five to check their oral bioavailability. On the basis of these QSAR models, five compounds (4-35, 4-36, 5-20, 5-21, and 5-22) have been predicted that may be the next synthetic target. These molecules also fulfill the conditions of Lipinski's rule of five.