Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-methoxyestradiol-3,17-O,O-bis-sulfamate.
The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH(2) with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.
Department of Pharmacy and Pharmacology & Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, U.K.
Fabrice
F
Jourdan
Mathew P
MP
Leese
Wolfgang
W
Dohle
Ernest
E
Hamel
Eric
E
Ferrandis
Simon P
SP
Newman
Atul
A
Purohit
Michael J
MJ
Reed
Barry V L
BV
Potter
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
C500344:2-methoxyestradiol-3,17-bis-O,O-sulfamate; D000970:Antineoplastic Agents; D014404:Tubulin; D004958:Estradiol; D003078:Colchicine