Vijaya Gracias

RING EXPANSION BY IN SITU TETHERING OF HYDROXY AZIDES TO KETONES : THE BOYER REACTION

Abstract Although alkyl azides can react with ketones to form ring-expanded lactams, the reaction suffers from poor generality and the need to use powerful Lewis acid promotion. The reactions of 1,2- and 1,3-hydroxyalkyl azides with ketones yield N -hydroxyalkyl lactams in high yields under the action of protic or Lewis acids such as BF 3 ·OEt 2 . The reaction appears to succeed due to the initial formation of a hemiketal, which then renders the attack of azide on an oxonium ion intramolecular. The scope of this reaction vis a vis ketone and hydroxyalkyl azide structure is discussed.

Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors

We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).

Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase

Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.