Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor

Abstract

Steroid sulfatase (STS) catalyzes the hydrolyis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analogue bearing an alpha,alpha-difluorosulfonamide moiety at the 3-position on the A-ring, compound , was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pK(a) of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was determined to be 8.05 using 19F NMR. Compound is a reversible inhibitor with a K(i) similar to that of its sulfonate analogue at pH 7.0. It is more potent than its non-fluorinated sulfonamide analogue and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.

Human sulfatases: A structural perspective to catalysis

“…Early studies focused on replacing the sulfate group of estrone or estradiol with O-, N-, or S-linked sulfate surrogates [44]. Efforts were made to design reversible inhibitors that are nonhydrolyzable analogs of E1-sulfate [50,51]. E1-sulfate analogs with a boronic acid substitution at the 3-position in lieu of the sulfate group were found to be good competitive inhibitors of STS [52].…”

Fluorine in medicinal chemistry: A review of anti-cancer agents

“…For example, fidarestat 113 and sorbinil 114 (anti-cancer/anti-diabetic) [113], brequinar 115 (antitumour/ immunosuppressive) [114], roflumilast 116 (anti-inflammatory/ chronic obstructive pulmonary diseases) [115], leflunomide 117 and VML-295 (LY293111) 118 (anti-cancer/psoriasis) [116], T0901317 119 and 2,4,6-trisubstituted pyridines 120 have been reported as potent farnesoid X receptor (FXR) modulators and they have emerged as target drugs for inflammation and cancers [117]. Fluorinated gonadotropin-releasing hormone (hGnRH) receptor antagonists 121 and 122 are in clinical development for the treatment of human reproductive diseases and gynecological cancer [118] and the steroid sulfatase inhibitors 123, 124 have recently been reported as more potent compounds than their non-fluorinated analogues 125, 126 as inhibitors of steroid dependent cancers [119].…”

Development of steroid sulfatase inhibitors

“…Taylor et al further applied the above design strategy to EMATE and synthesized the analogue 5n (Fig. 5), which bears an ,-difluorosulfonamide moiety at the 3-position on the A-ring of estrone (Liu et al, 2005). The replacement of the bridging O-atom of the sulfamate group in EMATE with an ,-difluoromethylene moiety was designed to render the resulting analogue nonhydrolyzable, but yet to still mimic EMATE.…”