A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure–activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.

A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCtheta inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbonitrile 3 resulted in the identification of compound 23e as a potent PKCtheta inhibitor with good selectivity over PKCdelta.

A series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles were prepared and evaluated as PKC theta inhibitors. Optimization resulted in the identification of compound 15 with an IC(50) value 0.44 nM for the inhibition of PKC theta with 150-fold selectivity over PKC delta. (C) 2009 Elsevier Ltd. All rights reserved.

The pyranonaphthoquinones (+)-7-deoxyfrenolicin B and (+)-7-deoxykalafungin were synthesized in four steps using an oxa-Pictet-Spengler cyclization that directly provided the natural (3a,5)-trans-substituted dihydronaphthopyrans with high diastereoselectivity. This outcome is in contrast to the unnatural (3a,5)-cis-substituted dihydronaphthopyrans reported under similar conditions for the syntheses of (+)-frenolicin B and (+)-kalafungin. Computational modeling is presented that provides insight into this unusual stereoselectivity.

Previous SAR studies of the diastereomers of LY301621 suggested the importance of a beta-turn conformation for biological activity. In the present study, cyclic analogs were designed and synthesized that possess Type II and II' beta-turns. Their biological activity will be discussed. (C) 1997 Elsevier Science Ltd.