9-cis-Retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists Rosana Alvarez, a M. Jesu´s Vega, a Sabrina Kammerer, b Aure´lie Rossin, b Pierre Germain, b Hinrich Gronemeyer b and Angel R. de Lera a, * a Departamento de Quı´mica Orga´ nica, Facultad de Quı´mica, Universidade de Vigo, 36200 Vigo, Spain b Department of Cell Biology and Singal Transduction, Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France Received 30 July 2004; accepted 30 August 2004 Abstract—Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner–Wadsworth–Emmons reaction afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of sig- nificant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction The hormone action of retinoic acid 1 and its 9-cis-iso- mer 2 in multicellular organisms is expressed through the activation of genetic networks governed by the binding of the ligand–cognate receptor complexes 1 to promoter regions of DNA. The retinoid families of nuclear proteins (RARs-retinoic acid receptors- and RXRs-retinoid X receptors-, both comprising isotypes a,b,c) act as ligand-inducible transcription factors, regu- lating physiological processes essential for embryonic development as well as for cell growth, differentiation, and death. trans-Retinoic acid (1) is the natural ligand for RAR, and its isomer 9-cis-retinoic acid (2) has high affinity for, and activates, both RAR and RXR. It is be- lieved that RARs and RXRs act mainly as RAR–RXR heterodimers, the functional units that also affect other cell signaling pathways, albeit RXR can also function autonomously. 2 The ability of retinoids 3,4 to regulate cell growth and in- duce differentiation throughout life has been demon- strated by the response of a large number of cancer cell lines in culture to retinoids and the therapeutic suc- cess of trans-retinoic acid 1 in the treatment of acute promielocytic leukemia (APL). 5 Concerns about secondary effects of retinoid therapy (retinoic acid syndrome, teratogenicity) has stimulated the search for novel retinoids incorporating structural modifications at the hydrophobic ring and/or the side chain, and these modifications oftentimes contribute to improve chemical stability. 4 Commonly the trimethylcy- clohexenyl ring is replaced by the lipophilic bioisostere 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. In addition, the presence of aryl rings as substitutes of ter- minal dienes imparts greater stability in some of the most active analogues, thus increasing the chances for therapeutical application. LGD1069 (bexarotene, Tar- gretin Ò ) 3 is the first synthetic RXR-selective agonist (rexinoid) approved for the treatment of cutaneous T- cell lymphoma. 6 Another common substitute of the hydrophobic ring is a 3,5-di-tert-butylbenzene, and this structure is present in some selected antiproliferative retinoids (Fig. 1). 7 Amide 4 and chalcone 5 are selective RAR ligands, and show induction of differentiation on the HL-60 promyelocytic cell line. 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.08.072 Keywords: 9-cis-Retinoic acid; RXR agonist; Nuclear receptor. * Corresponding author. Tel.: +34 986812316; fax: +34 986812556; e-mail: qolera@uvigo.es Bioorganic & Medicinal Chemistry Letters 14 (2004) 6117–6122