Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

Recent progress in the synthesis and investigation of the biological activities of cyclopeptide alkaloids is reviewed. New strategies have been devised to overcome some of the synthetic challenges inherent in the formation of strained paracyclophanes. However, issues remain which offer opportunities for the application of catalytic enantioselective organometallic reactions. Members of this class of natural products have been isolated from various parts of a wide variety of plants and researchers will likely continue to show great interest in their formation and function. The biological properties of certain members of this class warrant further investigation. To gain additional insight into these areas, continuing development of synthetic methodology will be essential.

Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.

A short and efficient total synthesis of isoroquefortine C, the 3,12-(Z)-isomer of roquefortine C, from L-tryptophan methyl ester hydrochloride and 4(5)-(hydroxy)methylimidazole hydrochloride is described.