Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies

A series of novel 9-substituted-3,7-dithia-5-azatetracyclo[9.2.1.02,10.04,8]tetradecen-4(8)-ones-6 have been synthesized by a stereoselective hetero-Diels–Alder reaction of 5-ylidene-4-thioxo-2-thiazolidone derivatives with norbornene-2. All the compounds have been evaluated for antitumor activity in in vitro human tumor cell lines, and 10 of them possessed significant and selective cytotoxicity (MGM log GI50 ∼ −4.17 to −4.98, for individual cell lines log GI50 up to −8). COMPARE analyses of differential growth inhibition patterns of compounds at the GI50 level showed high correlations with some of the antitubulin agents. The lipophilicity of the compounds was studied by RP-TLC and found to correlate well with calculated log P values. Docking and structure–activity relationship studies produced seven QSAR models with 2 or 3 variables, with correlation coefficients r2 > 0.9 and leave-one-out cross-validation correlation coefficients, q2 > 0.8.

Synthesis, anticancer activity, lipophilicity, and QSAR studies for new thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety and aryl- or heteroaryl-substituents are described.Figure optionsDownload as PowerPoint slide