Synthesis and DNA reactivity of alpha-hydroxylated metabolites of nonsteroidal antiestrogens.
Tamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1, 2-diphenylbut-1-ene], a nonsteroidal antiestrogen, induces liver tumors in rats by a genotoxic mechanism. The mechanism of DNA adduct formation is believed to proceed via the formation of a reactive carbocation at the alpha-position from the alpha-hydroxylated metabolite. Molecular mechanics calculations [Kuramochi, H. (1996) J. Med. Chem. 39, 2877-2886] have predicted that 4-substitution will affect the stability of the carbocation and thus will alter its reactivity toward DNA. We have synthesized the putative alpha-hydroxylated metabolites of 4-hydroxytamoxifen [(E)-1-(4-(2-(N, N-dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-3-hydroxy-2-phenyl but-1-ene] and idoxifene [(Z)-1-(4-iodophenyl)-3-hydroxy-2-phenyl-1-(4-(2-(N-pyrrolidino) ethoxy)phenyl)but-1-ene] and compared their reactivities with DNA with that of alpha-hydroxytamoxifen [(E)-1-(4-(2-(N, N-dimethylamino)ethoxy)phenyl)-3-hydroxy-1,2-diphenylbut-1-ene]. As predicted, the bis-hydroxylated compound reacted with DNA in aqueous solution at pH 5 to give 12-fold greater levels of adducts than alpha-hydroxytamoxifen, whereas alpha-hydroxyidoxifene gave one-half the number of adducts. The results demonstrate that idoxifene presents a significantly lower genotoxic hazard than tamoxifen for the treatment and prophylaxis of breast cancer.
Hardcastle
I R
IR
CRC Centre for Cancer Therapeutics and Section of Molecular Carcinogenesis, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, U.K.
Horton
M N
MN
Osborne
M R
MR
Hewer
A
A
Jarman
M
M
Phillips
D H
DH
D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004965:Estrogen Antagonists / Q000737:chemistry*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry
D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D004965:Estrogen Antagonists; D013629:Tamoxifen; C016601:afimoxifene