合成香豆素-7-胺基磺酸 3、4號位擴環衍生物作為類固醇硫酸酯酶抑制劑及其活性探討

Abstract

類固醇硫酸酯酶 (steroid sulfatase, STS)一般存在於人體組織器官中，可以調節雌酮硫酸鹽 (estrone sulfate, E1S)及硫酸脫氫表雄酮 (dehydroepiandrosterone sulfate, DHEAS)轉化為具活性的雌激素酮 (estrone, E1)及脫氫表雄酮 (dehydroepiandrosterone, DHEA)。相較於正常細胞，ERα+乳癌腫瘤組織之類固醇硫酸酯酶會大量表現，造成癌細胞的增生，因此，抑制類固醇硫酸酯酶可以間接降低類固醇雌激素含量，進而減少乳癌細胞的增生，達到治癒乳癌的效果。 研究顯示香豆素胺基磺酸鹽類 (coumarin-based sulfamates)的化合物可有效抑制類固醇硫酸酯酶的活性，而在先前的研究中發現，3-benzylaminocoumarin-7-O-sulfamates衍生物對於人類胎盤類固醇硫酸酯酶具有抑制效果，且以coumarin為核心之化合物對其3號位置進行衍生化可增加活性。因此在本研究中，試著針對coumarin進行擴環合成出兩系列化合物，第一系列之化合物為針對coumarin進行環的限制修飾所合成出之三環化合物56a–n。結果顯示，以三環化合物56為核心對苯環3號位進行修飾可以增加抑制類固醇硫酸酯酶的效果，其中以化合物56b活性最佳，對於人類胎盤及MCF-7細胞類固醇硫酸酯酶之IC50分別為0.95 nM及0.38 μM。另外，第二系列之化合物65為E1S之類似物，其同樣具有理想的抑制效果，對於人類胎盤及MCF-7細胞類固醇硫酸酯酶之IC50分別為2.98 nM及0.55 μM。 本研究證實針對coumarin進行環的限制修飾可以有效增加化合物對類固醇硫酸酯酶的作用，達到更佳的抑制活性。

Steroid sulfatase (STS) is one enzyme responsible for the hydrolysis of biological inactive estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) to the corresponding active estrone (E1) and dehydroepiandrosterone (DHEA), which could convert to steroids that exhibit estrogenic properties. STS is present in several human tissues and organs. Compared to the normal tissues, there are raised levels of STS in estrogen receptor-positive breast cancer, promoting the proliferation of cancer cells. Therefore, inhibiting the activity of STS will decrease the level of estrogenic hormones and inhibit the proliferation and development of breast cancer. Many studies have shown that coumarin-based sulfamate derivatives are potent STS inhibitors. In the previous work, we found that 3-benzylaminocoumarin-7-O-sulfamate derivatives could inhibit STS. Furthermore, structure modification at 3-position of coumarin could increase the activity of inhibition. As a result, in this study, two series of ring expansion were accomplished at 3, 4-positions of coumarin. First one was additional ring restriction coumarin to give tricycle compound 56a–n. The inhibitory activities of 56a–n were tested against MCF-7 cells and purified STS that was extracted from human placenta. Structure activity relationship (SAR) analysis revealed that the modification at 3-position of benzene ring improved inhibitory activity, where 56b was found to have the highest inhibitory activity against human placenta STS (IC50 = 0.95 nM) and MCF-7 cells STS (IC50 = 0.38 μM). The second series of compound was the mimic of E1S to provide compound 65, which was found to have good inhibitory activity against human placenta STS (IC50 = 2.98 nM) and MCF-7 cells STS (IC50 = 0.55 μM). Our results confirmed that the ring expansion of coumarin could increase the interaction between the inhibitors and STS, resulting in the better inhibitory activity.