TRITIUM LABELLING OF RETINOIC ACID ANALOG: PSORIASIS & CANCER CHEMOTHERAPY

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The role of retinoids such as all-trans-retinoic acid (ATRA), 13-cis-retinoic acid (13-cis-RA), and synthetic retinoic acid (RA) analogs in mediating cell growth and differentiation has generated interest in their pharmacological utility for treatment of dermatological diseases, such as psoriasis and acne, as well as for oncological applications, such as chemotherapy and chemoprevention. Several retinoids, among them ATRA, 13-cis-RA, and etretinate are currently marketed for treatment of dermatological diseases and are experimentally being evaluated for cancer applications. Although these retinoids have proven therapeutically effective in the treatment of such diseases, their toxicities have limited and/or prevented their use for prolonged periods. As a result of recent discoveries regarding the biological function of retinoids and retinoid receptors, it is now possible to design compounds with improved therapeutic indices. This RA analog synthesized in this project shows high selectivity between the retinoic acid receptors (RAR) and the retinoid X receptors (RXR)1. It has already been used in direct binding studies and competitive binding with 3H 9-cis RA, yielding similar Kd values for 9-cis RA and ATRA. Additionally it was used to elucidate the relationship between ligand binding, RAR/RXR heterodimerization, and retinoic-dependent transcription. The natural ligand, 9-cis-retinoic acid, shows some physical and chemical instability, and is inappropriate for the binding studies program. This more stable analog will be used for high throughput binding and transactivation assays for the RXR ligands. 1."Syntheses of Isotopically Labeled 4-[1-(3,5, 5,8,8, -Pentamethyl-5,6,7, 8-tetrahydro-2-naphthyl) ethenyl] benzoic Acid (LGD1069), A Potent Retinoid X Receptor-Selective Ligand", Zhang, L.; Badea, B. A.; Enyeart, D.; Berger, E.M.; Mais, D.E.; and Boehm, M.; J. Labelled Compd. Radiopharm., 36, 701 (1995). User Details: Experiment Details: User Number: 1704 Tritiation City, State: Wallingford, CT HPLC Funding Source: Industry NMR Charge: $5122.53 4 days Program Income: $4872.34 1 compound