Synthesis and Reactivity of 3,4-Di-OHTAM-o-quinone
Chem. Res. Toxicol., Vol. 13, No. 1, 2000 61
phenyl]]-1-(4-iodophenyl)-2-phenyl-1-butene}. Org. Prep. Proced.
Int. 26, 343-346.
quinoids with respect to the biological effects of tamoxifen
are not known; however, given the direct link between
tamoxifen therapy and the enhanced risk of endometrial
cancer, the potential for formation of redox-active and/
or electrophilic metabolites from tamoxifen needs to be
explored.
(19) Teitel, S., and O’Brien, J . P. (1976) Selective removal of an
aromatic methylenedioxy group. J . Org. Chem. 41, 1657-1658.
(20) Curtin, D. Y., and Harder, R. J . (1960) Stereochemistry and
reactions with hydroxy ion and with silver oxide of 2-bromo-4-
phenyl cyclohexanol and 1-methyl-2-bromo-4-phenyl cyclohex-
anols. J . Am. Chem. Soc. 82, 2357.
(21) Iverson, S. L., Shen, L., Anlar, N., and Bolton, J . L. (1996)
Bioactivation of estrone and its catechol metabolites to quinoid-
glutathione conjugates in rat liver microsomes. Chem. Res.
Toxicol. 9, 492-499.
(22) Bolton, J . L., Acay, N. L., and Vulkomanovic, V. (1994) Evidence
that 4-allyl-o-quinones spontaneously rearrange to their more
electrophilic quinone methides: Potential bioactivation mecha-
nism for the hepatocarcinogen safrole. Chem. Res. Toxicol. 7, 443-
450.
Ack n ow led gm en t. This research was supported by
NIH Grant CA-79870 (J .L.B.) and CA-83124 (R.B.v.B.).
We thank Mr. Richard Dvorak for performing high-
resolution mass spectrometry measurements.
Refer en ces
(1) J ordan, V. C. (1993) A current view of tamoxifen for the treatment
and prevention of breast cancer. Br. J . Pharmacol. 110, 507-
517.
(2) Fisher, B., Costantino, J . P., Wickerham, D. L., Redmond, C. K.,
Kavanah, M., Cronin, W. M., Vogel, V., Robidoux, A., Dimitrov,
N., Atkins, J ., Daly, M., Wieand, S., Tan-Chiu, E., Ford, L., and
Wolmark, N. (1998) Tamoxifen for prevention of breast cancer:
Report of National Surgical Adjuvant Breast and Bowel Project
1 Study. J . Natl. Cancer Inst. 90, 1371-1388.
(3) Smith, L. L., and White, I. N. (1998) Antiestrogen therapy:
uncertainties and risk assessment. Oncology 12, 14-22.
(4) Killackey, M. A., Hakes, T. B., and Price, V. K. (1985) Endometrial
adenocarcinoma in breast cancer patients receiving antiestrogen.
Cancer Treat. Rep. 69, 237-238.
(5) Henderson, B. E., Ross, R., and Bernstein, L. (1988) Estrogens
as a cause of human cancer: The Richard and Hinda Rosenthal
Foundation Award Lecture. Cancer Res. 48, 246-253.
(6) Hellmann-Blumberg, U., Cartner, M. G., Wurz, G. T., and
DeGregorio, M. W. (1998) Intrinsic reactivity of tamoxifen and
toremifene metabolites with DNA. Breast Cancer Res. Treat. 50,
135-141.
(7) Hemminki, K., Rajaniemi, H., Lindahl, B., and Moberg, B. (1996)
Tamoxifen-induced DNA adducts in endometrial samples from
breast cancer patients. Cancer Res. 56, 4374-4377.
(8) Hemminki, K., Rajaniemi, H., Koskinen, M., and Hansson, J .
(1997) Tamoxifen-induced DNA adducts in leukocytes of breast
cancer patients. Carcinogenesis 18, 9-13.
(9) Phillips, D. H., Potter, G. A., Horton, M. N., Hewer, A., Crofton-
Sleigh, C., J arman, M., and Venitt, S. (1994) Reduced genotoxicity
of [D5-ethyl]tamoxifen implicates R-hydroxylation of the ethyl
group as a major pathway of tamoxifen activation to a liver
carcinogen. Carcinogenesis 15, 1487-1492.
(10) Moorthy, B., Sriram, P., Pathak, D. N., Bodell, W. J ., and
Randerath, K. (1996) Tamoxifen metabolic activation: Compari-
son of DNA adducts formed by microsomal and chemical activa-
tion of tamoxifen and 4-hydroxytamoxifen with DNA adducts
formed in vivo. Cancer Res. 56, 53-57.
(23) Andrews, D. L., Williams, G. S., Mahoney, J . C., and West, J . R.
(1999) DNA fragmentation during exposure of rat cerebella to
ethanol under hypoxia imposed in vitro. J . Neurobiol. 38, 82-
92.
(24) Sandoval, M., Zhang, X. J ., Liu, X., Mannick, E. E., Clark, D. A.,
and Miller, M. J . (1997) Peroxynitrite-induced apoptosis in T84
and RAW 264.7 cells: Attenuation by L-ascorbic acid. Free Radical
Biol. Med. 22, 489-495.
(25) Williard, P. G., and Fryhle, C. B. (1980) Boron trihalide-methyl
sulfide complexs as convenient reagents for dealkylation of aryl
ethers. Tetrahedron Lett. 21, 3731-3734.
(26) Node, M., Nishide, K., Fuji, K., and Fujita, E. (1980) Hard acid
and soft nucleophile system. 2. Demethylation of methyl ethers
of alcohol and phenol with an aluminium halide-thiol system. J .
Org. Chem. 45, 4275-4277.
(27) Osborne, C. K., Wiebe, V. J ., McGuire, W. L., Ciocca, D. R., and
DeGregorio, M. W. (1992) Tamoxifen and the isomers of 4-hy-
droxytamoxifen in tamoxifen-resistant tumors from breast cancer
patients. J . Clin. Oncol. 10, 304-310.
(28) Brewster, M. E., Huang, M. J ., Pop, E., and Bodor, N. (1995)
Isomeric interconversions in tamoxifen and related compounds-
an AM1 study. Int. J . Quantum Chem. 55, 343-352.
(29) Katzenellenbogen, J . A., Carlson, K. E., and Katzenellenbogen,
B. S. (1985) Facile geometric isomerization of phenolic non-
steroidal estrogens and antiestrogens: limitations to the inter-
pretation of experiments characterizing the activity of individual
isomers. J . Steroid Biochem. 22, 589-596.
(30) McCage, R., Leclercq, G., Legros, N., Goodman, J ., Blackburn,
M., J arman, M., and Foster, A. B. (1989) Derivatives of tamoxifen.
Dependence of antiestrogenicity on the 4-substituent. J . Med.
Chem. 32, 2527-2533.
(31) Collins, D. J ., Hobbs, J . J ., and Emmens, C. W. (1971) Anties-
trogenic and antifertility compounds. 4. 1,1,2-Triarylalkan-1-ols
and 1,1,2-triarylalkenes containing basic ether group. J . Med.
Chem. 14, 952.
(32) Abul-Hajj, Y. J ., and Cisek, P. (1988) Catechol estrogen adducts.
J . Steroid Biochem. 31, 107-110.
(11) Dehal, S. S., and Kupfer, D. (1995) Evidence that catechol 3,4-
dihydroxytamoxifen is a proximate intermediate to the reactive
species binding covalently to protein. Cancer Res. 56, 1283-1290.
(12) Dehal, S. S., and Kupfer, D. (1999) Cytochrome P-450 3A and
2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and
3-hydroxytamoxifen (Droloxifene) yielding tamoxifen catechol:
involvement of catechols in covalent binding to hepatic proteins.
Drug Metab. Dispos. 27, 681-688.
(13) Lim, C. K., Lamb, J . H., Yuan, Z. X., and Smith, L. L. (1994)
Identification of epoxide metabolites of tamoxifen by on-line liquid
chromatography-electrospray ionization mass spectrometry. Bio-
chem. Soc. Trans. 22, S165.
(33) J acobsohn, M. K., Byler, D. M., and J acobsohn, G. M. (1991)
Isolation of estradiol-2,3-quinone and its intermediary role in
melanin formation. Biochim. Biophys. Acta 1073, 1-10.
(34) Monks, T. J ., and Lau, S. S. (1997) Biological reactivity of
polyphenolic-glutathione conjugates. Chem. Res. Toxicol. 10,
1296-1313.
(35) Liberato, D. J ., Byers, V. S., Dennick, R. G., and Castagnoli, N.
(1981) Regiospecific attack of nitrogen and sulfur nucleophiles
on quinones derived from poison oak/ivy catechols (urushiols) and
analogues as models for urushiol-protein conjugate formation. J .
Med. Chem. 24, 28-33.
(36) Iverson, S. L., Hu, L. Q., Vukomanovic, V., and Bolton, J . L. (1995)
The influence of the para-alkyl substituent on the isomerization
of o-quinones to p-quinone methides: Potential bioactivation
mechanism for catechols. Chem. Res. Toxicol. 8, 537-544.
(37) Kalyanaraman, B., Premovic, P. I., and Sealy, R. C. (1987)
Semiquinone anion radicals from addition of amino acids, pep-
tides, and protein to quinones derived from oxidation of catechols
and catecholamines: An ESR stabilization study. J . Biol. Chem.
262, 11080-11087.
(38) Zhang, F., Chen, Y., Pisha, E., Shen, L., Xiong, Y., van Breemen,
R. B., and Bolton, J . L. (1999) The major metabolite of equilin,
4-hydroxyequilin, autoxidized to an o-quinone which isomerizes
to the potent cytotoxin 4-hydroxyequilenin-o-quinone. Chem. Res.
Toxicol. 12, 204-213.
(14) Lim, C. K., Yuan, Z. X., Lamb, J . H., White, I. N. H., De Matteis,
F., and Smith, L. L. (1994) A comparative study of tamoxifen
metabolism in female rat, mouse and human liver microsomes.
Carcinogenesis 15, 589-593.
(15) Fan, P. W., Zhang, F., and Bolton, J . L. (2000) 4-Hydroxylated
metabolites of the antiestrogens tamoxifen and toremifene are
metabolized to unusually stable quinone methides. Chem. Res.
Toxicol. 13, 45-52.
(16) NIH Guidelines for the Laboratory Use of Chemical Carcinogens,
NIH Publication 81-2385 (1981) U.S. Government Printing Office,
Washington, DC.
(17) Gauthier, S., Mailhot, J ., and Labrie, F. (1996) New highly
stereoselective synthesis of (Z)-4-hydroxytamoxifen and (Z)-4-
hydroxytoremifene via McMurry reaction. J . Org. Chem. 61,
3890-3893.
(39) Bolton, J . L., and Shen, L. (1996) p-Quinone methides are the
major decomposition products of catechol estrogen o-quinones.
Carcinogenesis 17, 925-929.
(18) McCague, R., Potter, G. A., and J arman, M. (1994) An efficient,
large-scale synthesis of Idoxifene {(E)-1-[4-[2-(N-pyrrolidino)-