Steroid sulfatase inhibitors

Abstract

Steroid sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3-hydroxy steroids, which are inactive transport or precursor forms of the active 3-hydroxy steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential new therapeutic agents for the treatment of estrogen- and androgen-dependent disorders. Indications range from cancers of the breast, endometrium and prostate to androgenetic alopecia and acne. In this review, we give a comprehensive summary of the current knowledge and problems in the field of medicinal chemistry of STS inhibitors. The various types of inhibitors are presented and their structure-activity relationships are discussed. In addition to potent arylsulfamate-based, irreversible inhibitors, novel types of reversible inhibitors were recently discovered. The recent publication of the X-ray structure of STS will further boost research activities on this attractive target.

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

“…However, recent finding indicated that the third ring appears to be predominately in the boat conformation rather than previously proposed chair conformation based on temperature factors (B-factors) and electron density map results [79]. With the advent of this new finding regarding the conformation of the 7-membered ring on compound 30 it can now be explained that its higher potency (IC 50 value of 8 nM and K i value of 40 nM) than EMATE (IC 50 = 25 nM and K i = 670 nM) is attributed to the tendency to mimic the steroidal CD-ring; perhaps, better hydrophobic interactions due to favorable binding to the active site of the enzyme are in play [61,85,86].…”

“…estrone sulfate, to the active hormones by STS represents the first step in the local production of estrogen and androgens. Therefore, the inhibition of this enzyme (STS), which should decrease the biosynthesis of active hormones, has been a new therapeutic option in the treatment for hormone-dependent diseases [55][56][57][58] such as breast, endometrial and prostate cancers, acne and androgenic alopecia [53,[59][60][61]. Since STS catalyzes the hydrolysis of sulfate monoester bonds in a range of physiological substrates, the incorporation of a sulfamate ester group linked to an aryl ring was considered to be key strategy in the development of potent STS inhibitors [42,[62][63][64][65].…”

“…Compound 30 ( Fig. 3) is a nonsteroidal irreversible STS inhibitor and is the most potent of a series of tricyclic COUMATE developed with annulated carbocylic ring systems at positions 3 and 4 [41,61,68] with a very acceptable toxicological profile. It has an equipotent in vivo STS activity compared to estrone-3-O-sulfamate (EMATE), a potent, active sitedirected, irreversible steroidal STS inhibitor [81].…”

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

“…[10][11][12] The multiple roles of STS in generating estrogenic steroids suggest that the inhibition of STS in patients with HDBC could deliver a level of estrogen deprivation sufficient to halt the progress of the disease. Many potent inhibitors of STS have been developed during the past decade, [9,[13][14][15] of which the nonsteroidal STX64 (1, BN83495, Figure 1) is a 'first-in-class' candidate that underwent a phase I trial for the treatment of postmenopausal women with advanced HDBC. [16,17] Clinical 4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported.…”

“…The products were extracted with EtOAc (2 75 mL), the combined organic fractions were washed with water (50 mL) and brine (50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. (4-Benzyloxy-3-chlorophenyl)acetic acid (14). The title compound was prepared in manner similar to that for 12, using 3-chloro-4-hydroxyphenylacetic acid (14.22 …”