Recent studies have demonstrated the multi-mechanism anti-tumor effects of 2-substituted estradiol bis-sulfamates and highlighted a number of potential advantages that such compounds possess relative to the corresponding estradiols, which include 2-methoxyestradiol (2-MeOE2, Panzem ™) a drug in Phase II clinical trials. 2-Methoxy- (2-MeOE2bisMATE, STX140, 1) and 2-ethyl-estradiol bis-sulfamate (2-EtE2bisMATE, STX243, 2) display potent anti-proliferative and anti-angiogenic activity and also function as inhibitors of steroid sulphatase (STS), a clinical target for the treatment of hormone dependent breast cancer. In order to generate novel agents with anti-proliferative activity against human breast cancer cells we have synthesised a number of 2-substituted estradiol 3-O-sulfamate analogues with oxygenated side chains tethered at C-17 as bio-isosteric replacements of the 17-O-sulfamate group of the bisMATEs. The 17β-(2-hydroxyethyl) compound 3 in which the hydroxyl group can function as both hydrogen bond donor or acceptor displays excellent activity against the proliferation of MCF-7 cells (GI50 <0.5 μM) whilst its O-substituted derivatives, methyl ether 4 (GI50 >10 μM) and sulfamate 5 (GI50 5.6 μM), were relatively inactive. The ethyl ester 6 also displayed only modest activity (GI50 4.2 μM) whilst the analogous keto compound 7 (GI50 0.32 μM) proved to be a suitable bio-isostere for the 17-O-sulfamate. The simple 17-O-methoxyethyl ether 8 (GI50 0.52 μM) also showed good activity against the proliferation of MCF-7 cells. We have thus synthesised a number of novel D-ring modified 2-substituted estradiol-3-O-sulfamates with promising in vitro activity, and confirmed both the importance of H-bond acceptor interactions around the D-ring and the steric demands of the site of action. The potential of the sulfamoylated estradiol derivatives for development as anti-cancer agents was reinforced by the activity of 2-EtE2bisMATE 2 in a MDA-MB-231 xenograft model in female athymic nude mice. An oral dose of the 2 at 40 mg/kg (28d) caused regression and prolonged inhibition of tumour growth that continued after cessation of dosing (6/6 animals) and tumour disappearance (1/6 animals) with no observed toxicity.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]