Abstract
Benzo[c]phenanthridine (BCP) derivatives were identified as topoisomerase I (TOP-I) targeting agents with pronounced antitumor activity. In this study, hologram-QSAR, 2D-QSAR and 3D-QSAR models were developed for BCPs on topoisomerase I inbibitory activity and cytotoxicity against seven tumor cell lines including RPMI8402, CPT-K5, P388, CPT45, KB3-1, KBV-1and KBH5.0. The hologram, 2D, and 3D-QSAR models were obtained with the square of correlation coefficient R2 = 0.58 − 0.77, the square of the crossvalidation coefficient q2 = 0.41 − 0.60 as well as the external set’s square of predictive correlation coefficient r2 = 0.51 − 0.80. Moreover, the assessment method based on reliability test with confidence level of 95% was used to validate the predictive power of QSAR models and to prevent over-fitting phenomenon of classical QSAR models. Our QSAR model could be applied to design new analogues of BCPs with higher antitumor and topoisomerase I inhibitory activity.
Highlights
The topoisomerases (TOP) are enzymes involved in DNA replication, repair, transcription, recombination and segregation
Among the groups showing the resistance to topoisomerase I (TOP-I) activity, the substances similar to benzo[c]phenanthridine synthesized by Lavoie and colleagues (Figure 1) have shown significant cytotoxicity [3,4,5,6,7,8,9,10,11]
QSAR models on topoisomerase inhibitory activity and cytotoxicity of RPMI8402, KB3-1 cell-lines were used for further investigation on application set
Summary
The topoisomerases (TOP) are enzymes involved in DNA replication, repair, transcription, recombination and segregation. Among the groups showing the resistance to TOP-I activity, the substances similar to benzo[c]phenanthridine synthesized by Lavoie and colleagues (Figure 1) have shown significant cytotoxicity [3,4,5,6,7,8,9,10,11]. Over 130 compounds have been synthesized but the QSAR studies on this group are still rare and its application is limited [12,13]. A dataset of 137 benzo[c]phenanthridine (BCP) analogues with TOP-I inhibitory activity and antitumor activity against seven cell lines, including RPMI8402, CPT-K5, P388, CPT45, KB3-1, KBV-1 and KBH5.0, were chosen for hologram-QSAR (H-QSAR), 2D-QSAR as well as. By combining three QSAR methods, we expect that the theoretical results can decrease the error of the prediction and offer some useful information for designing and screening more potential antitumor compounds with less time and cost
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