Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

An efficient discovery strategy by combining diversity oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460(TaxR) (EC50 < 1.0 mu M), which exhibits much less toxicity toward normal cells (EC50 > 100 mu M against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects.