設計合成3-芐胺基香豆素-7-O-胺基磺酸類衍生物作為類固醇硫酸酯酶抑制劑

Design and Synthesis of 3-Benzylaminocoumarin-7-O-Sulfamate Derivatives as Steroid Sulfatase Inhibitors

方愉(Yue Hng)

指導教授 ： 梁碧惠

國立臺灣大學/醫學院/藥學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201701586

摘要

類固醇硫酸酯酶（steroid sulfatase, STS）之功能為調節雌酮硫酸鹽（estrone sulfate, E1S）轉化為雌激素酮（estrone, E1）及硫酸脫氫表雄酮（dehydroepiandrosterone sulfate, DHEAS）轉化為脫氫表雄酮（dehydroepiandrosterone, DHEA）的關鍵角色。類固醇硫酸酯酶一般存在於人類的組織與器官中。不過與正常細胞相較時，癌化的ERα+乳癌腫瘤之類固醇硫酸酯酶活性會大量表現。因此，抑制類固醇硫酸酯可間接降低誘導乳癌細胞增長的類固醇雌激素含量，達到治愈乳癌的效果。

先前的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。因此在本研究中，我們設計合成了3-benzylaminocoumarin-7-O-sulfamates並對其進行構效關係的研究探討。首先以3-aminocoumarins與苯甲醛進行還原氨化反應得到一系列的3-benzylaminocoumarins，接著進行磺胺酰化反應得到最終產物，既3-benzylaminocoumarin-7-O-sulfamates。

3-benzylaminocoumarin-7-O-sulfamates的抑制活性及構效關係的探討直接以MCF-7乳癌細胞及純化後的人類胎盤類固醇硫酸酯酶進行，發現活性最佳者為3-(2,3-dimethoxybenzyl)aminocoumarin-7-O-sulfamate (28j)，其IC50為130 nM。為了更進一步了解化合物28j的結構限制，合成了3-(2,3- dimethoxyphenethyl)aminocoumarin-7-O-sulfamate（30）、3-(2,3-dimethoxy- benzamido)coumarin-7-O-sulfamate （32） 及3-(2,3-dimethoxybenzyl)-5-oxo-1,3,4,5- tetrahydrochromeno[3,4-c]pyridine-8-yl sulfamate （35）並測試其對於類固醇硫酸酯酶的抑制活性，發現以coumarin為核心之化合物中其3號位置衍生化可增加活性，但些微結構的修飾可能導致活性消失，針對coumarin 3號位置進行剛性結構修飾有助於維持其抑制活性。

關鍵字

STS ； 類固醇硫酸酯酶 ； 香豆素胺基磺酸鹽 ； 3-芐胺基香豆素-7-O-胺基磺酸鹽

並列摘要

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.

並列關鍵字

STS ； steroid sulfatase ； coumarin-based sulfamates ； 3-benzylaminocoumarin-7-O-sulfamates

參考文獻

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