Synthesis of aryl sulfamate and phenol small peptide derivatives using a multidetachable sulfamate linker strategy

Introduction Breast cancer is the most frequent cancer among women in the U.S., representing 31% of all newly diagnosed cancers in 2006. It is estimated that 75% of breast tumors express the estrogen receptor (ER) in a significant amount of cells. In these cases, it is possible to use hormone therapy as a treatment, alone or as an adjuvant to classical radioor chemotherapy. Hormone therapy can consist of either an ER antagonist (antiestrogen) or an inhibitor of the biosynthesis of estradiol (E2), the most potent endogenous estrogen. This work focuses on the second strategy, with steroid sulfatase (STS) and type 1 17β-hydroxysteroid dehydrogenase (17β-HSD1) as target enzymes. STS, a membrane enzyme widely distributed in the body and often overexpressed in breast tumors, catalyzes the transformation of estrone sulfate, inactive on ER, into estrone (E1), which is active. 17β-HSD1, expressed in aggressive breast tumors, transforms E1 into E2. Arylsulfamates are known irreversible inhibitors of STS and phenols are inhibitors of 17β-HSD1 in addition to being reversible inhibitors of STS. To address the need to rapidly synthesize arylsulfamate and phenols as inhibitors for these enzymes, our laboratory has developed the multidetachable sulfamate linker (see Figure 1) for solid phase synthesis. When treated with an acidic solution, this linker yields arylsulfamates whereas when submitted to a nucleophilic treatment, phenol is obtained. Nine small model libraries, 5 of sulfamates and 4 of phenols, were synthesized using this linker