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.
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.
Jourdan
Fabrice
F
Medicinal Chemistry, Department of Pharmacy and Pharmacology & Sterix Ltd, University of Bath, Claverton Down, Bath, UK BA2 7AY.
Bubert
Christian
C
Leese
Mathew P
MP
Smith
Andrew
A
Ferrandis
Eric
E
Regis-Lydi
Sandra
S
Newman
Simon P
SP
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004583:Electrons; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D013451:Sulfonic Acids; D014404:Tubulin; C005741:sulfamic acid