3196 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Letters
(12) Adams, J . B.; Garcia, M.; Rochefort, H. Estrogenic effects of
physiological concentrations of 5-androstene-3â,17â-diol and its
metabolism in MCF-7 human breast cancer cells. Cancer Res.
1981, 41, 4720-4726.
(13) Dauvois, S.; Labrie, F. Androstenedione and androst-5-ene-3â,-
17â-diol stimulate DMBA-induced mammary tumourssrole of
aromatase. Breast Cancer Res. Treat. 1989, 13, 61-69.
(14) Labrie, F.; Be´langer, A.; Simard, J .; Luu-The, V.; Labrie, C.
DHEA and peripheral androgen and estrogen formation: intra-
crinology. Ann. N. Y. Acad. Sci. 1995, 774, 16-28.
showed no significant inhibition, as expected, since it
lacks the pharmacophore for STS inhibition. However,
DASI 4 showed nearly complete inhibition (g98%) after
3 h of treatment. These results clearly indicate that the
concept of a DASI works in principle and in vivo. We
also studied the in vivo activities of 7, which is the best
DASI in vitro. After 3 h of treatment, 7 reduced plasma
estradiol level by 68% (Figure 3), a potency similar to
that of YM511 (Figure 3). Like 4, 7 is also highly active
against the rat liver sulfatase activity, showing an
inhibition of g98% after 3 h of treatment (Figure 3).
Clearly, structural optimization can lead to highly
potent in vivo active dual inhibitors with nanomolar
potencies, and further optimization is in progress.
In conclusion, we have validated in this work the
novel concept of a dual aromatase and STS inhibitor.
For the first time, a small series of DASI candidates
have been prepared and found to possess high potency
against both enzymes in vitro. In vivo, one example (4)
shows inhibitory activities against both aromatase and
STS. Compound 7, a m-bromo derivative of 4, shows not
only high potency against STS but also a similar potency
to YM511 against aromatase, demonstrating that the
potency of this class of DASIs can be further optimized.
This strategy should be applicable to other AIs and
should allow the therapeutic potential of dual inhibition
of estrogen formation in breast tumors to be assessed.
(15) Labrie, F. Intracrinology. Mol. Cell. Endocrinol. 1991, 78, C113-
C118.
(16) Poortman, J .; Andriesse, R.; Agema, A.; Donker, G. H.; Schwarz,
F.; Thijssen, J . H. H. Adrenal androgen secretion and metabo-
lism in postmenopausal women. In Adrenal Androgens; Genaz-
zani, A. R., Thijssen, J . H. H., Siiteri P. K., Eds.; Raven Press:
New York, 1980; pp 219-240.
(17) Bird, C. E.; Murphy, J .; Boroomand, K.; Finnis, W.; Dressel, D.;
Clark, A. F. Dehydroepiandrosterone: Kinetics of metabolism
in normal men and women. J . Clin. Endocrinol. Metab. 1978,
47, 818-822.
(18) Reed, M. J .; Noel, C. T.; J ones, D. L.; J acobs, H. S.; Scanlon, M.
J .; J ames, V. H. T. The use of non-radiolabelled steroid infusions
to investigate the origin of oestrone sulphate in postmenopausal
women. Horm. Metab. Res. 1986, 18, 779-783.
(19) Howarth, N. M.; Purohit, A.; Reed, M. J .; Potter, B. V. L. Estrone
sulfamates: potent inhibitors of estrone sulfatase with thera-
peutic potential. J . Med. Chem. 1994, 37, 219-221.
(20) Selected latest examples. (a) Fischer, D. S.; Woo, L. W. L.;
Mahon, M. F.; Purohit, A.; Reed, M. J .; Potter, B. V. L. D-ring
modified estrone derivatives as novel potent inhibitors of steroid
sulfatase. Bioorg. Med. Chem. 2003, 11, 1685-1700. (b) Fischer,
D. S.; Chander, S. K.; Woo, L. W. L.; Fenton, J . C.; Purohit, A.;
Reed, M. J .; Potter, B. V. L. Novel D-ring modified steroid
derivatives as potent, non-oestrogenic steroid sulphatase inhibi-
tors with in vivo activity. J . Steroid Biochem. Mol. Biol. 2003,
84, 343-349.
(21) Kolli, A.; Chu, G.-H.; Rhodes, M. E.; Inoue, K.; Selcer, K. W.;
Li, P.-K. Development of (p-O-sulfamoyl)-N-alkanoyl-phenylalkyl
amines as non-steroidal estrone sulfatase inhibitors. J . Steroid
Biochem. Mol. Biol. 1999, 68, 31-40.
(22) (a) Woo, L. W. L.; Howarth, N. M.; Purohit, A.; Hejaz, H. A. M.;
Reed, M. J .; Potter, B. V. L. Steroidal and nonsteroidal sulfa-
mates as potent inhibitors of steroid sulfatase. J . Med. Chem.
1998, 41, 1068-1083. (b) Woo, L. W. L.; Purohit, A.; Malini, B.;
Reed, M. J .; Potter, B. V. L. Potent active site-directed inhibition
of steroid sulfatase by tricyclic coumarin-based sulfamates.
Chem. Biol. 2000, 7, 773-791.
(23) (a) Purohit, A.; Hejaz, H. A. M.; Woo, L. W. L.; van Strien, A.
E.; Potter, B. V. L.; Reed, M. J . Recent advances in the
development of steroid sulphatase inhibitors. J . Steroid Biochem.
Mol. Biol. 1999, 69, 227-238. (b) Nussbaumer, P.; Lehr, P.;
Billich, A. 2-Substituted 4-(thio)chromenone 6-O-sulfamates:
potent inhibitors of human steroid sulfatase. J . Med. Chem.
2002, 45, 4310-4320.
(24) (a) Ciobanu, L. C.; Luu-The, V.; Poirier, D. Nonsteroidal
compounds designed to mimic potent steroid sulfatase inhibitors.
J . Steroid Biochem. Mol. Biol. 2002, 80, 339-353. (b) Nuss-
baumer, P.; Bilban, M.; Billich, A. 4,4′-Benzophenone-O,O′-
disulfamate: a potent inhibitor of steroid sulfatase. Bioorg. Med.
Chem. Lett. 2002, 12, 2093-2095.
(25) Okada, M.; Yoden, T.; Kawaminami, E.; Shimada, Y.; Kudoh,
M.; Isomura, Y.; Shikama, H.; Fujikura, T. Studies on aromatase
inhibitors. I. Synthesis and biological evaluation of 4-amino-4H-
1,2,4-triazole derivatives. Chem. Pharm. Bull. 1996, 44, 1871-
1879.
(26) Woo, L. W. L.; Lightowler, M.; Purohit, A.; Reed, M. J .; Potter,
B. V. L. Heteroatom-substituted analogues of the active site-
directed inhibitor estra-1,3,5-(10)-trien-17-one-3-sulfamate in-
hibit estrone sulfatase by a different mechanism. J . Steroid
Biochem. Mol. Biol. 1996, 57, 79-88.
Ack n ow led gm en t. This work was supported by
Sterix Ltd. We thank Ms. A. C. Smith for technical
assistance.
Refer en ces
(1) Unpublished Cancer Research U.K. data, 2002.
(2) Theobald, A. J . Management of advanced breast cancer with
endocrine therapy: the role of the primary healthcare team. Int.
J . Clin. Pract. 2000, 54, 665-669.
(3) Wells, S. A.; Santen, R. T.; Lipton, A.; Haagensen, D. E., J r.;
Ruby, E. J .; Harvey, H.; Dilley, W. G. Medical adrenalectomy
with aminoglutethimide clinical studies in postmenopausal
patients with metastatic breast carcinoma. Ann. Surg. 1978, 187,
475-484.
(4) Brodie, A. Aromatase inhibitors in breast cancer. Trends En-
docrinol. Metab. 2002, 13, 61-65.
(5) Santner, S. J .; Feil, P. D.; Santen, R. J . In situ estrogen
production via the estrone sulfatase pathway in breast tumors:
relative importance vs the aromatase pathway. J . Clin. Endo-
crinol. Metab. 1984, 59, 29-33.
(6) Yamamoto, T.; Kitawaki, J .; Urabe, M.; Honjo, H.; Tamura, T.;
Noguchi, T.; Okada, H.; Sasaki, H.; Tada, A.; Terashima, Y.;
Nakamura, J .; Yoshihama, M. Estrogen productivity of en-
dometrium and endometrial cancer tissuesinfluence of aro-
matase on proliferation of endometrial cancer cells. J . Steroid
Biochem. Mol. Biol. 1993, 44, 463-468.
(7) Noel, C. T.; Reed, M. J .; J acobs, H. S.; J ames, V. H. T. The
plasma concentration of oestrone sulphate in postmenopausal
women: lack of diurnal variation, effect of ovariectomy, age and
weight. J . Steroid Biochem. 1981, 14, 1101-1105.
(8) J ames, V. H. T.; McNeill, J . M.; Lai, L. C.; Newton, C. J .;
Ghilchik, M. W.; Reed, M. J . Aromatase activity in normal breast
and breast tumor tissues: in vivo and in vitro studies. Steroids
1987, 50, 269-279.
(9) Tseng, L.; Mazella, J .; Lee, L. U.; Stone, M. L. Oestrogen
sulphatase and oestrogen sulphotransferase in human primary
mammary carcinoma. J . Steroid Biochem. 1983, 19, 1413-1417.
(10) Naitoh, K.; Honjo, H.; Yamamoto, T.; Urabe, M.; Ogino, Y.;
Yasumura, T.; Nambara, T. Oestrone sulphate and sulphatase
activity in human breast cancer and endometrial cancer. J .
Steroid Biochem. 1989, 33, 1049-1054.
(11) Chetrite, G. S.; Cortes-Prieto, J .; Philippe, J . C.; Wright, F.;
Pasqualini, J . R. Comparison of estrogen concentrations, estrone
sulfatase and aromatase activities in normal, and in cancerous,
human breast tissues. J . Steroid Biochem. Mol. Biol. 2000, 72,
23-27.
(27) Okada, M.; Iwashita, S.; Koizumi, N. Efficient general method
for sulfamoylation of a hydroxyl group. Tetrahedron Lett. 2000,
41, 7047-7051.
(28) Yue, W.; Brodie, A. Mechanisms of the actions of aromatase
inhibitors 4-hydroxyandrostenedione and fadrozole, and amin-
ioglutethimide on aromatase in J EG-3 cells in culture. J . Steroid
Biochem. Mol. Biol. 1997, 63, 317-328.
J M034033B