| Summary: | 碩士 === 臺北醫學大學 === 藥學研究所 === 95 === Two classes of 1-aroylindoles and 1-aroylindolines were synthesized as potent anticancer agents based on the bioisosterism concept utilizing combretastatin A-4 (CA-4) as a template. 1-Aroylindoles were prepared by reacting substituted indoles with 3,4,5-trimethoxybenzoic anhydride or 3,4,5-trimethoxybenzoyl chloride. 1-Aroylindolines were prepared by reducing substituted indoles to indolines and then reacting with 3,4,5-trimethoxybenzoyl chloride or 3,4,5-trimethoxy-2-nitrobenzoic acid. 2-23 belong to 1-aroylindoles and 25-30 belong to 1-aroylindolines. Structure-activity relationship study was also discussed.
2, 4, 7, 11, 13, 14, 24 and 26 showed moderate cytotoxicities with IC50 values of 210-652 nM in inhibiting oral epidermoid carcinoma KB cell growth in vitro. 9, 12 and 25 exhibited potent cytotoxicities with IC50 values of 20 nM, 8 nM, and 87 nM, respectively. 22 showed a slight increase in activity with IC50 values of 1.1 nM as compared to CA-4 (IC50 values of 1.65 nM). The most potent compound 23 showed strong antiproliferative activity against KB cell line with IC50 values of 0.16 nM, 10-fold more potent than CA-4.
The structure-activity relationship study of these compounds revealed that the methoxy group at the C-5 position could be replaced with an electron-donating group such as methyl (4), 5,6-methylenedioxy (7), amino (11) or N,N-dimethylamino (12) while retaining strong cytotoxicity. Addition of a methyl group at the C-2 position in 1-aroylindole increased the cytotoxic potency. Substitution at the C-3 position led to a substantial loss of potency. The introduction of 4-amino and 4-hydroxy substitution in the 1-aroylindole gave 22 and 23, which contribute to significant extent for maximal activity by mimicking AVE-8063 and combretastatin A-4 respectively.
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