George E. Lee

Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode.

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.

Thienamycin. A solution of the stereochemical problem

Abstract A new nitrone-based synthesis of β-lactams is described which makes provision for the 1-hydroxyethyl moiety in the potent antibiotic thienamycin. Moreover, the relative stereochemical features of the natural product are defined in a step involving the cycloaddition of a nitrone with methyl crotonate.

A Synthesis of γ-Ketocarboxylic Acids and its Application in the Preparation of Benzo [B]Furans

Abstract The aldol addition-pinacol rearrangement sequence starting with 1,2-bis(trimethylsilyloxy)cyclobutene and a ketal or acetal provides facile entry into a series of substituted 1,3-cyclopentadiones.2 This, combined with the known propensity for 1,3-diketones to undergo cleavage reactions, affords a useful sequence for the synthesis of γ-ketocarboxylic acids: Application of this sequence is demonstrated in a new synthesis of 2,3-dihydrobenzo [b] furan (ergo, benzo[b] furan).