Chem. Rev. 1999, 99, 723−744 723 Comparative QSAR Analysis of Estrogen Receptor Ligands Hua Gao,† John A. Katzenellenbogen,‡ Rajni Garg,† and Corwin Hansch*,† Departments of Chemistry, Pomona College, Claremont, California 91711, and University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801 Received April 27, 1998 (Revised Manuscript Received November 18, 1998) Contents I. Introduction I. Introduction 723 In recent years, the need for agents for the treat- II. Methods 725 ment of hormone-responsive cancers and the mecha- III. Results 726 nistic toxicological studies of environmental pollut- 1. Estradiol Derivatives 726 ants have sparked a great deal of scientific interest and research into the chemical and biological inter- A. Relative Binding Affinities (RBA) of 726 16R-Substituted Estradiols with Rat actions between estrogen receptors and their ligands. Uterine Estrogen Receptor at 0 °C Breast cancer is the most frequently diagnosed 1 B. Relative Binding Affinities of 727 cancer in women and a major cause of cancer. Since 11â-Substituted Estradiols with Mouse estrogens are known to play a role in the develop- Uterine Estrogen Receptor ment and growth of many breast cancers, a logical C. Relative Binding Affinities of 727 approach for the treatment of estrogen-sensitive 17R-Substituted Estradiols with Rat breast cancer is the use of antiestrogens that block Uterine Estrogen Receptor at 0 °C the interaction of estrogens with their specific D. Relative Binding Affinities of 17R-XCHd 728 receptor. Several classes of antiestrogens have been CH-estradiols with Rat Uterine Estrogen developed for the treatment of breast cancer, but Receptor unfortunately, although the initial response of breast E. Relative Binding Affinities of 11â-, 16R-, 729 cancer to hormone therapy can be substantial, resis- and 17R-Substituted Estradiols with Lamb tance to estrogen antagonist therapy often devel- Uterine Estrogen Receptor ops.2,3 Tamoxifen (Nolvadex), the antiestrogen most F. Relative Binding Affinities of 730 frequently used in breast cancer hormone therapy 7R-Undecylestradiol Derivatives with Calf has mixed agonist-antagonist properties; other more Uterine Estrogen Receptor recently developed antiestrogens, such as ICI G. Relative Binding Affinities of 730 182,780, are pure antiestrogens and may prove to be Multisubstituted Estradiols with Receptors more effective in breast cancer treatment.4 Anties- of Mouse Mammary Epithelial Cells trogens are also being studied as agents to prevent 2. Nonsteroidal Compounds 731 breast cancer in women at high risk.5 A. Metahexestrol and Hexestrol Derivatives 731 Estrogens are also widely prescribed in meno- B. Indenes and Indenones 732 pausal women as hormone replacement therapy to C. 2-Phenylindole Derivatives 733 maintain bone mineral density and preserve cardio- D. Benzothiophenes 734 vascular health. The use of agents, such as Raloxifene E. Triphenylacrylonitrile Derivatives 737 (Evista), that have a favorable balance of agonist F. Increase in the Proliferation of MCF-7 737 activities in certain tissues (bone, liver, vasculature) Cells (EC ) with Triphenylacrylonitriles and antagonist activities in other tissues (uterus and 50 6,7 G. 1,1-Diphenylethylenes 738 breast) is favored for such uses because of their reduced risk in promoting tumor development and H. Antiestrogenicity of 1,1-Diphenylethylenes 739 growth in these tissues, and there are many active I. Estrogenic Activity of 739 programs of research in academic and industrial 4,4′-Dihydroxydiphenylmethanes in Rats laboratories aimed at the development of such tissue- J. MCF-7 Cell Proliferation by Simple 740 selective estrogens. Phenols in Cells Free of Natural Estrogens The finding that compounds from the environment, of both synthetic and natural origin, can interfere K. MCF-7 Cell Proliferation by 4-HOC6H4C- 741 (X)(Y)C H -4′-OH with sexual development and reproductive function 6 4 has led to intense investigations of these endocrine- IV. Discussion 741 disruptive substances.8 Many (though not all9,10) V. Acknowledgment 743 endocrine disrupters are estrogens and exert agonist VI. References 743 and antagonist effects through the estrogen recep- tor: those that are synthetic include pesticides, food antioxidants, and metabolites of nonionic surfac- * To whom correspondence may be addressed. 11 † Pomona College. tants; naturally occurring ones are plant secondary ‡ University of Illinois. metabolites and mold metabolites.8 Among the latter 10.1021/cr980018g CCC: $35.00 © 1999 American Chemical Society Published on Web 02/19/1999 724 Chemical Reviews, 1999, Vol. 99, No. 3 Gao et al. Hua Gao received his Ph.D. in Pharmaceutical Sciences at the University Rajni Garg received her M.Sc. in Chemistry (1984) from Meerut University of Southern California. He joined Professor Corwin Hansch in 1995 as a and M.Phil. (1988) degree from Delhi University, India. Her M.Phil. postdoctoral research associate and worked with BioByte Corporation as dissertation work was on peptide synthesis. She was a faculty member a scientist. Currently, he is working with MDS Panlabs as a scientist in in the Chemistry Department of Birla Institute of Technology and Science, Computational Chemistry and Informatics. His research interests include Pilani, India, from 1991 to 1996, where she taught organic and physical QSAR, computer-assisted drug design (CADD), and natural products. chemistry. She received her Ph.D. degree in 1996 under the supervision of Professor S. P. Gupta. Her doctoral work was on QSAR Studies on Anti-HIV Agents. In February 1997, she joined Professor Corwin Hansch as a postdoctoral researcher, and she is currently involved in building a C-QSAR databank. Her research interests include QSAR and computer- assisted drug design. John Katzenellenbogen did his undergraduate and graduate studies in chemistry at Harvard University with E. J. Corey, receiving his Ph.D. degree in 1969 for work on the development of methods for stereospecific olefin synthesis and their application to natural product synthesis. That same year he joined the faculty of the Department of Chemistry at the University of Illinois, where he is now the Swanlund Professor of Chemistry. Dr. Corwin Hansch received his undergraduate education at the University Katzenellenbogen’s research interests have focused on various aspects of Illinois and his Ph.D. in Organic Chemistry from New York University of the structure, function, and use of steroid receptors: He prepared affinity in 1944. After working with the DuPont Company, first on the Manhattan labeling agents for the estrogen receptor and used them to study receptor Project and then in Wilmington, DE, he joined the Pomona College faculty structure, function, and dynamics; he developed an extensive series of in 1946. He has remained at Pomona except for two sabbaticals: one at steroid receptor-based agents labeled with fluorine-18 and technetium- the Federal Institute of Technology in Zurich with Professor Prelog and 99m for imaging receptor-positive tumors of the breast and prostate by the other at the University of Munich with Professor Huisgen. The Pomona radioimaging methods; and he has designed fluorescent probes for steroid group published the first paper on the QSAR approach relating chemical receptors that enable receptor dynamics to be followed in individual cells. structure with biological activity in 1962. Since then, QSAR has received John Katzenellenbogen has trained more than 70 doctoral and postdoctoral widespread attention. In Current Contents (1981/41) he was named as students and published more than 300 articles. He is a fellow of the one of the 300 most cited scientists out of over one million publishing in American Academy of Arts and Sciences. He received the 1995 Aebersold all fields of science for the period 1965−1978. In 1986, Hansch was cited Award of the Society of Nuclear Medicine and a Cope Scholar Award in Current Contents as being one of the 250 most cited primary authors from the American Chemical Society in 1999. for 1984. He is an honorary fellow of the Royal Society of Chemistry and recently received the ACS Award for Computers in Chemical and category are common natural secondary plant Pharmaceutical Research for 1999. metabolitessflavanoids and ligninssthat are present at high levels in common foods, especially those tion, and transcriptional activation on the other.12 derived from soy and whole grains; these compounds The binding of ligands to the hormone-binding do- are considered to be beneficial to human health. main of ER stabilizes the interaction of the receptor The estrogen receptor (ER), the target of these with target sequences in the regulatory region of agents, is a ligand-modulated transcription factor these genes. This binding may be either directly to that regulates the activity of certain genes.12 A specific DNA enhancer sequences or, in some cases, member of the nuclear hormone receptor gene su- to AP1 enhancers through the AP1 transcription perfamily, ER has a multidomain structure, with two factors Fos and Jun. The activation or repression of conserved domains that are responsible for DNA these genes by the ligand receptor complex is then binding on one hand, and ligand binding, dimeriza- mediated by the recruitment by ER of a variety of Comparative QSAR Analysis of Estrogen Receptor Ligands Chemical Reviews, 1999, Vol. 99, No. 3 725 coregulatory proteins that interact with components With this background in the quantitative structure of the basal transcriptional complex