The crystal structure of the ligand-binding domain of RARb, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARb to bind more bulky agonists. Accordingly, we identified a ligand that shows RARb selectivity with a 100-fold higher affinity to RARb than to a or c isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARa, c antagonist and an RARb agonist. In addition, we demonstrate how to generate an RARb antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARb-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARb in vitro and in animal models.

No abstract

An asymmetric 10-step synthesis is developed affording the title compound (XII) in 18% overall yield. The use of commercial sodium cyclopentadienide (I) improves the yield of (III) 3-fold. The enantiomer of (XII) and the adenine analogue are prepared in the same manner, whereas the thymine and iodouracil analogues are prepared prior to the development of the optimized oxidation/methylenation sequence ((VII) → (X)). The novel compound (XII) is a potent inhibitor of hepatitis B virus with relatively low cytotoxicity. -(BISACCHI, G. S.; CHAO, S. T.; BACHARD, C.; DARIS, J. P.; INNAIMO, S.; JACOBS, G. A.; KOCY, O.; LAPOINTE, P.; MARTEL, A.; MERCHANT, Z.; SLUSARCHYK, W. A.; SUNDEEN, J. E.; YOUNG, M. G.; COLONNO, R.; ZAHLER, R.; Bioorg. Med. Chem. Lett. 7 (1997) 2, 127-132; Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA; EN)

No abstract

No abstract