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

Poly(aspartic acids) of different chain lengths (11, 14, 18,24, 30,52, 58, = 115) were prepared, for the use in aminoglycoside-induced nephrotoxicity inhibition studies, some in their pure L-or D-configuration and in pure a-linkage form by the polymerization of a-amino acid Ncarboxyanhydride (NCA) derivatives with a variety of dialkyl aspartate molecules as primary amine initiators. The primary amine chosen served as an internal reference in the 'H NMR spectrum for the estimation of the degree of polymerization (chain length) in these molecules. Poly(aspartic acids) with varying amounts of D and L asymmetric centres and in pure a-linkage form were also prepared. Poly[(a-co-& (L-co-D) aspartic acid] was prepared by a simplified thermal polymerization procedure for biological studies and also to study the tacticity effects in its 13C NMR spectrum. A qualitative correlation was demonstrated between the retention times from gel-permeation chromatographic analysis and the 'H NMR method used to estimate the polymer chain length. * L

Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding activity. This resulted in compounds with a 6-fold increased potency.

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)