Synthesis, Crystal Structure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene Ju ¨ rgen O. Daiss, † Christian Burschka, † John S. Mills, ‡ John G. Montana, ‡ Graham A. Showell, ‡ Ian Fleming, § Claudine Gaudon, | Diana Ivanova, | Hinrich Gronemeyer, | and Reinhold Tacke* ,† Institut fu ¨ r Anorganische Chemie, Universita ¨ t Wu ¨ rzburg, Am Hubland, D-97074 Wu ¨ rzburg, Germany, Paradigm Therapeutics Ltd., 162 Cambridge Science Park, Milton Road, Cambridge CB4 0GP, U.K., Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, U.K., and Institut de Ge ´ ne ´ tique et de Biologie Mole ´ culaire et Cellulaire (IGMBC), CNRS/INSERM/ULP, BP 10142, F-67404 Illkirch Cedex, C. U. de Strasbourg, France Received December 27, 2004 Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaph- thalene skeleton of the RXR-selective retinoid agonist bexarotene (1a) leads to disila- bexarotene (1b). Compound 1b was synthesized in a multistep synthesis, starting from 1,2- bis(chlorodimethylsilyl)ethane. The identity of 1b was established by elemental analyses and multinuclear NMR studies, and the C/Si analogues 1a and 1b (and an intermediate in the synthesis of 1b) were structurally characterized by single-crystal X-ray diffraction. Furthermore, 1a and 1b were studied for their interaction with retinoid X receptors. Although the twofold sila-substitution of 1a resulted in significant differences in the molecular structures of 1a and 1b, disila-bexarotene (1b) was shown to be a highly potent RXR agonist. Introduction Bexarotene (Targretin, 1a) is an RXR-selective ret- inoid that is in therapeutic use for treatment of cutane- ous T-cell lymphoma. 1-4 In context with our systematic studies on sila-substituted drugs, 5,6 we were interested in the biological properties of the silicon analogue disila- bexarotene (1b). As almost all sila-analogues of drugs studied so far are antagonists, 5 the twofold sila- substitution of the retinoid agonist bexarotene was particularly challenging. The molecular events by which RXR and other members of the nuclear receptor family regulate tran- scription of cognate gene programs are, at least in principle, reasonably well understood. 7 The signaling cascade relies on a precisely orchestrated recruitment and dissociation of transcription factors and molecular machineries to target gene promoters, which is initiated upon ligand binding. Multiple transcription activation, protein interaction, and crystallographic studies have revealed structural features of nuclear receptor ligand binding domains that are generated upon binding of agonists, antagonists, mixed agonists/antagonists, or inverse agonists, demonstrating an unexpected potential to modulate nuclear receptor action by ligand design. 8 * To whom correspondence should be addressed. Phone: +49-931-888-5250. Fax: +49-931-888-4609. E-mail: r.tacke@ mail.uni-wuerzburg.de. † Universita ¨t Wu ¨ rzburg. ‡ Paradigm Therapeutics Ltd. § Cambridge University. | IGBMC. (1) Syntheses and biological studies: (a) Boehm, M. F.; Heyman, R. A.; Zhi, L. (Inventors), Ligand Pharmaceuticals Inc., San Diego, CA. PCT Int. Pat. Appl. WO 93/21146 A1 (Oct 28, 1993); Chem. Abstr. 1994, 120, 217004k. (b) Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. J. Med. Chem. 1994, 37, 2930-2941. (c) Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. J. Med. Chem. 1995, 38, 3146-3155. (d) Nadzan, A. M.; Boehm, M. F.; Zhang, L.; Badea, B. A.; Zhi, L.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; McClurg, M. R.; Davies, P. J. A.; Heyman, R. A. Eur. J. Med. Chem. 1995, 30 (Suppl.; Proceedings of the 13th International Symposium on Medicinal Chemistry, 1994), 519s-533s. (e) Dawson, M. I.; Jong, L.; Hobbs, P. D.; Cameron, J. F.; Chao, W.; Pfahl, M.; Lee, M.-O.; Shroot, B.; Pfahl, M. J. Med. Chem. 1995, 38, 3368-3383. (f) Zhang, L.; Badea, B. A.; Enyeart, D.; Berger, E. M.; Mais, D. E.; Boehm, M. F. J. Labeled Comp. Radiopharm. 1995, 36, 701-712. (g) Kizaki, M.; Dawson, M. I.; Heyman, R.; Elstner, E.; Morosetti, R.; Pakkala, S.; Chen, D.-L.; Ueno, H.; Chao, W.; Morikawa, M.; Ikeda, Y.; Heber, D.; Pfahl, M.; Koeffler, H. P. Blood 1996, 87, 1977-1984. (h) Farmer, L. J.; Zhi, L.; Jeong, S.; Kallel, E. A.; Croston, G.; Flatten, K. S.; Heyman, R. A.; Nadzan, A. M. Bioorg. Med. Chem. Lett. 1997, 7, 2747-2752. (i) Shirley, M. A.; Wheelan, P.; Howell, S. R.; Murphy, R. C. Drug Metab. Disp. 1997, 25, 1144-1149. (j) Sun, S.-Y.; Yue, P.; Dawson, M. I.; Shroot, B.; Michel, S.; Lamph, W. W.; Heyman, R. A.; Teng, M.; Chandraratna, R. A. S.; Shudo, K.; Hong, W. K.; Lotan, R. Cancer Res. 1997, 57, 4931-4939. (k) Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. J. Org. Chem. 2001, 66, 5772-5782. (l) Howell, S. R.; Shirley, M. A.; Grese, T. A.; Neel, D. A.; Wells, K. E.; Ulm, E. H. Drug Metab. Disp. 2001, 29, 990-998. (m) Zhang, C.; Hazarika, P.; Ni, X.; Weidner, D. A.; Duvic, M. Clin. Cancer Res. 2002, 8, 1234-1240. 3192 Organometallics 2005, 24, 3192-3199 10.1021/om040143k CCC: $30.25 © 2005 American Chemical Society Publication on Web 05/20/2005