S-160202

A novel set of S16020 derivatives was designed applying structure-activity relationships (SAR).The newly synthesized compounds were subjected to in vitro cytostatic activity screening against human kidney cancer (cell line A498), human lung cancer (cell line A549) and normal human dermal fibroblasts (cell line NHDF).Two 6H-pyrido[4,3-b]carbazole derivatives exhibited stronger potency against both investigated cell lines than the reference compounds ellipticine and doxorubicin.

Looking to the recent roles of topoisomerases in various types of cancers, in the present paper, a quant. structure-activity relationship model, based on genetic function approximation (GFA) method, was developed using 41 olivacine derivatives as inhibitors of topoisomerase IIβ (Topo IIβ).The best predictive GFA model explained the biol. activity of the training and test sets with correlation coefficient values (r²) of 0.747 and 0.549, resp., and a significant cross-validated correlation coefficient (q²) of 0.525.The model suggested pos. correlation between activity and descriptors, namely partition coefficient (ALogP), electrostatic energy, number of hydrogen bond acceptors and number of rotatable bonds, while those of neg. correlations with Jurs RPCG, Jurs TASA and PHI.Furthermore, a common feature-based pharmacophore model for these inhibitors was also developed which comprised of five features, namely one H-bond acceptor, two ring aromatic, one pos. ionizable and one hydrophobic group.Screening of a large database for natural compounds, using both these developed models, led to identification of the pyrrole derivative, namely 1-(2-(dimethylamino)ethyl)-3-hydroxy-4-(4-methoxy-2-methylbenzoyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-2(5H)-one (compound ID: STOCK1N-31995) with a predicted IC₅₀ value of 0.3 × 10^-6 μM as most potent inhibitor of Topo IIβ.The result of virtual screening was further validated using mol. dynamics (MD) simulation anal.Thus, a 15 ns MD simulation anal. revealed high stability and effective binding of 1-(2-(dimethylamino)ethyl)-3-hydroxy-4-(4-methoxy-2-methylbenzoyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-2(5H)-one within the active site of Topo IIβ.