Synthesis of indole-ring fluorine-labeled analogs of LY333531, an isoform-selective inhibitor of protein kinase C

Two fluorine-labeled analogs of LY333531, a potent, ATP-competitive, and is oform-selective inhibitor of protein kinase C-beta, have been prepared. F-1 9-NMR labels were placed on the indole rings to probe for differences in th e catalytic domains of the PKC isoforms, The fluorinated bis(indolyl)maleim ide was prepared by a Steglich coupling of 5-fluoroindole with N-methyl dic hloromaleimide, and was coupled to a chiral, aliphatic dimesylate prepared from 1 (S)-[(2R)-1,4-dioxaspiro[4.5]decanyl]3-buten-1-ol. The coupling-macr ocyclization step was performed by slow addition of a mixture of the bis(in dolyl)maleimide and the dimesylate to a suspension of cesium carbonate in D MF, and adjustment of the functionality provided the final labeled analog 1 . A simplified analog 2 was prepared from diiodohexane by a similar procedu re. Compounds 1 and 2 had IC(50)'s of 5 and 6 nM, respectively, against PKC -beta(II), acid of 57 and 79 nM, respectively, against PKC-alpha. (C) 1999 Elsevier Science S.A. All rights reserved.