| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 102 === A series of novel thiochromeno[2,3-c]quinolin-12-ones with a potential side chains had been synthesized by a various synthetic route via Pfitzinger reaction, intramolecular cyclization, and nucleophilic substitution. The biological activity had been preliminarily studied for cell cytotoxicity, topoisomerases inhibition, and in vitro cytotoxicity against NCI’s 60 cell line human tumor screen. The results indicated that compounds N7, N14, N18 and N19 exhibited significant potent inhibitory effects in TOPs-mediated DNA by using TOP activity assays. Twenty-six compounds were selected by the NCI for one dose screening program and further studies on compounds N2, N7, N14, N19, and N25 where the curves cross these lines represent the interpolated values to cause 50% growth inhibition, total growth inhibition, and 50% cell killing, respectively. Among of them, compounds N7 and N14 not only showed the outstanding cytotoxic effects (Both values of GI50 were 1.66 M) but also exhibited dual inhibitions of TOP I/II (the range of IC50 values were between 1-10 M). Interestingly, compound N2 revealed poor cytotoxicity and mild TOPs inhibition but disclosed the high selective ratio (9.091) against breast cancer (GI50 from 0.04 M to 10.10 M). The exact mechanism of how this pharmacophore contributes to its activity is still unclear, however, the group in the extended arm of the novel tetracyclic thiochromenoquinolones might contribute to proper binding to the residues within the TOP-mediated DNA complexes.
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