| Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 105 === Recent findings have shown that steroid sulfatase (STS) is a potential novel target for breast cancer treatment. STS plays a crucial role in the regulation of steroid hormone concentrations which is responsible for the conversion of estrone sulfate (E1S) to estrone (E1), as well as dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA). STS is present in several human tissues and organs. However, in contrast to normal tissues, STS enzyme activity in ERα-positive breast cancer tumors is overexpressed. Therefore, inhibition of STS is a new approach to abate estrogenic steroids that stimulate the proliferation and development of breast cancer.
Previous studies have shown that coumarin-based sulfamates are capable to inhibit STS enzyme activities. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate analogues were designed and synthesized. Reductive amination of 3-aminocoumarin and benzaldehydes, followed by NaBH3CN treatment, a series of 3-benzylamino coumarins were obtained. 3-benzylaminocoumarins were further subjected to sulfamoyl chloride in THF to give the desired 3-benzylaminocoumarin-7-O-sulfamate derivatives.
The inhibitiory activity of 3-benzylaminocoumarin-7-O-sulfamate derivatives 28a-q were tested directly with MCF-7 cells and purified STS enzyme which was extracted from human placenta. 3-(2,3-dimethoxybenzyl)aminocoumarin-7-O-sulfamate (28j) was found to have highest inhibition activity against STS (IC50 = 130 nM). In order to study conformation of compound 28j, 3-(2,3-dimethoxyphenethyl) aminocoumarin-7-O-sulfamate (30), 3-(2,3-dimethoxy-benzamido)coumarin-7-O- sulfamate (32) and 3-(2,3-dimethoxybenzyl)-5-oxo-1,3,4,5-tetrahydrochromeno[3,4-c] pyridine-8-yl sulfamate (35) were synthesized. Structure activity relationship (SAR) analysis revealed that in coumarin structure modification at 3-position improved inhibitory activity, however subtle change of substation moiety might cause activity loss. Structure with rigid modification at 3-position of coumarin derivatives could maintain STS inhibitory activity.
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