Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates: synthesis, in vitro evaluation and computational modelling

• Published in: Organic & biomolecular chemistry 2008-01, Vol.6 (22), p.4108-4119
• Main Authors: Jourdan, Fabrice, Bubert, Christian, Leese, Mathew P, Smith, Andrew, Ferrandis, Eric, Regis-Lydi, Sandra, Newman, Simon P, Purohit, Atul, Reed, Michael J, Potter, Barry V L
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Computer Simulation; Electrons; Heterocyclic Compounds - chemistry; Humans; Hydrogen Bonding; Models, Molecular; Sulfonic Acids - chemical synthesis; Sulfonic Acids - chemistry; Sulfonic Acids - metabolism; Sulfonic Acids - pharmacology; Tubulin - metabolism
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b810300c

The potent activity of 2-substituted estra-1,3,5(10)-triene-3-O-sulfamates against the proliferation of cancer cells in vitro and tumours in vivo highlights the therapeutic potential of such compounds. Optimal activity is derived from a combination of a 2-XMe group (where X = CH(2), O or S), a 3-O-sulfamate group in the steroidal A-ring and a H-bond acceptor around C-17 of the D-ring. Herein, we describe the synthesis and anti-proliferative activities of a series of novel 2-substituted estra-1,3,5(10)-triene-3-O-sulfamates bearing heterocyclic substituents (oxazole, tetrazole, triazole) tethered to C-17. In vitro evaluation of these molecules revealed that high anti-proliferative activity in breast and prostate cancer cells lines (GI(50) of 340-850 nM) could be retained when the heterocyclic substituent possesses H-bond acceptor properties. A good correlation between the calculated electron density of the heterocyclic ring and anti-proliferative activity was observed. Docking of the most active compounds into their putative site of action, the colchicine binding site of tubulin, suggests that they bind through a different mode to the previously described bis-sulfamate derivatives and 1 and 2, which possess similar in vitro activity.