Computer-aided Design, Synthesis And Antitumor Activities Of Novel DNA Topoisomerase I Inhibitors

Malignant tumor is a serious threat to human health. It's well known that traditional chemotherapeutic drugs are unsatisfactory in the clinical treatment of most solid tumors due to their high toxicities and drug resistancy. With the success of Topotecan and Irinotecan in clinic, DNA topoisomerase I (Topo I) inhibitors have been validated as a series of very promising anticancer drugs due to their high potencies, broad anticancer spectrum and good specificities. However, such camptothecin(CPT) derivatives also suffer from metabolic instability, drug resistancy, serious side effects, etc. The non-CPT Topoâ… inhibitors are chemically stable and are promising to overcome such disadvantages. Therefore, it has become a promising field in chemotherapy to develop novel non-CPT Topoâ… inhibitors.To develop non-CPT Topoâ… inhibitors, this thesis includes three parts of work: Firstly, 3D-QSAR has been studied on 63 indenoisoquinoline Topoâ… inhibitors against prostate carcinoma cell DU-145 using CoMFA and CoMSIA methods. The resulting CoMFA and CoMSIA models had a cross-validated coeffiecient q² of 0.630 and 0.635 respectively, which showed strong predictive ability. The analysis of the 3D contour plots provided smooth and interpretable explanation of the structure-activity relationship, which will guide the design of novel compounds with relatively higher activity against human prostate cancer.Secondly, a novel series of indenoquinolines have been successfully discovered via scaffold hopping technology. Twenty-eight novel title compounds(22-49)were obtained with an optimized and versatile synthetic route. The cytotoxic effects of these compounds were tested in four human tumor cell lines, and all the title compounds(except 26 and 47) have shown promising activities, especially IC₅₀ values of 22,23,27,41,45 and 49 against all the four kind of tumor cell lines are approximately 1.0μg/mL.Thirdly, a series of novel Topo I inhibitors have been designed and synthesized starting from our leading compound SM-1 obtained from previous virtual high throughput screening studies in our group. Twelve title compounds (60-71) were obtained in good yield by an optimized six-step route. The cytotoxic effects of these compounds were tested in three human tumor cell lines, and compounds 63,65 and 61 displayed a selective inhibition on the growth of MDA-MB-435 with IC50 value of 2.38, 4.52, 4.73μg/mL respectively. The results of the present study in this thesis provide useful information for the design of non-CPT Topo I inhibitors and may be further utilized to help the developments of more potent antitumor drug candidates.