Steroidal and Nonsteroidal Sulfamates as Potent Inhibitors of Steroid Sulfatase

Abstract

Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

“…42 It is interesting to note that oestrogen sulphamates are also potent irreversible inhibitors of steroid sulphatase (STS), an enzyme responsible for the production of biologically active oestrogens in hormone-dependent breast, ovarian, and endometrial cancer cells. [43][44][45] The importance of STS in the progression of hormone-dependent tumours has been well documented. 43,44 It has been reported previously that C-2-substituted sulphamoylated oestrogens, such as 2-MeOEMATE and 2-MeOE2bisMATE, also inhibited STS enzyme both in vitro and in vivo.…”

“…[43][44][45] The importance of STS in the progression of hormone-dependent tumours has been well documented. 43,44 It has been reported previously that C-2-substituted sulphamoylated oestrogens, such as 2-MeOEMATE and 2-MeOE2bisMATE, also inhibited STS enzyme both in vitro and in vivo. 46,47 2-Ethyl-substituted compounds such as 2-EtE2-MATE and 2-EtE2bisMATE also inhibit STS activity with IC 50 values of 0.92 and 0.9 lM, respectively, in placental microsomes.…”

Geometry optimization of steroid sulfatase inhibitors - the influence on the free binding energy with STS

“…The first potent inhibitor based on the coumarin scaffold with significantly reduced estrogenic properties was 4-methyl-coumarin-7-O-sulfamate (1), Fig. 1 (COUMATE), which exhibited good activity with an IC 50 value of 380 nM when evaluated against placental microsomes [4]. Further modification of its structure led to a wide range of more potent compounds based on tricyclic coumarin derivatives containing sulfamate moiety that mimic the ABC rings of the natural substrate, e.g., 667-COUMATE (2), Fig.…”

“…In 2016, the same research group synthesized a series of fluorinated 3-phenylcoumarin-7-O-sulfamates [10]. The most active compounds designing so far-3-(3,4-difluorophenyl)-coumarin-7-O-sulfamate (4) The described above process of development of new steroid sulfatase inhibitors is expensive, time consuming, and requires collaboration of experts from different disciplines, such as: biology, chemistry, biochemistry, pharmacology, etc. However, according to recently recommended ideas in designing new drugs [11], this challenging process could be supported by a computational chemistry [12,13].…”

Biosynthesis of Coumarin Glycosides by Transgenic Hairy Roots ofPolygonum multiflorum

“…The chemical structures of all the compounds were elucidated by a comparison of their melting point, 1 H NMR and 13 C NMR, data with literatures. [9][10][11][12][13][14][15] Compounds 13 and 14 were biosynthesized from substrates 4 and 5 under the same process in the literature. 8) Compound 15 was identified by MS and NMR spectra.…”