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Synthesis and DNA reactivity of alpha-hydroxylated metabolites of nonsteroidal antiestrogens

Lookup NU author(s): Dr Ian HardcastleORCiD

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Abstract

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 α-position from the α-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 α-hydroxylated metabolites of 4-hydroxytamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-3-hydroxy-2-phenylbut-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 α-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 α-hydroxytamoxifen, whereas α-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.


Publication metadata

Author(s): Hardcastle IR, Horton MN, Osborne MR, Hewer A, Jarman M, Phillips DH

Publication type: Article

Publication status: Published

Journal: Chemical Research in Toxicology

Year: 1998

Volume: 11

Issue: 4

Pages: 369-374

Print publication date: 12/03/1998

ISSN (print): 0893-228X

ISSN (electronic): 1520-5010

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/tx970198+

DOI: 10.1021/tx970198+


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