| Summary: | 博士 === 中國醫藥大學 === 藥物化學研究所博士班 === 97 === The purpose of this study is to develop compounds with potential anticancer activity as new drug candidate. This thesis consists of two parts. In the first part, four different skeletons of YC-1 derivatives [furopyrazole derivatives (11-22, 28-36), thienopyrazole derivatives (42-45, 50-53), selenopyrazole derivatives (67-72, 75-77), and indazole derivatives (99−118, 123−128)] were synthesized in order to expand the substance patent’s inclusion of YC-1 and find new candidate with better anticancer activity than YC-1, and constructed their SAR in NCI-H226 and A498 cells. Compound 13 (CLC107), 44 (CLC015), 69 (CLC005), and 127 (CLC802a) were chosen for evaluation against 60 human cancer cell lines (the NCI-60) and COMPARE program analysis, and indicated that four compounds were with great development value since they possessed novel mechanism of action different from existing anticancer drugs. Finally compound 127 was proved to demonstrate anticancer activity similar to YC-1 in animal model, it is thus a new candidate of YC-1 in drug development.
In the second part, the problem of 2-phenyl-4-quinolone derivatives in pharmacokinetics is resolved. In order to improve solubility problem, a phosphoric acid was attempted to be attached to 4-ketone of 2-phenyl-4-quinolone, and thus phosphate monosodium salts of 2-phenyl-4-quinolone derivatives were successfully created, which were expected to be applied by po and iv routes in clinics.
Among 2-phenyl-4-quinolone derivatives, we focus on compound 8 which demonstrated the most significant antitumor activity. According to the data of Pharmacokinetics, compound 35 was proved to be transformed in vivo to compound 8 (CHM-1). After the assessment of safety pharmacology of compound 35 in enzyme activity assay and receptor binding assay, we predict it is very effective and safe drug while there should not be too many side effects in clinical trials. Besides, it showed excellent antitumor activity in SKOV-3 Xenograft SCID mice model and CT-26 colon adenocarcinoma Balb/c mice orthotopic model. It is confirmed that compound 35 (CHM-1-P-Na) is a drug candidate for further development as a potential anticancer agent in the clinic. We hope this series of compounds can successfully become clinical therapeutic agents which are beneficial to human beings.
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