183554-59-8Relevant articles and documents
Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: Sulfonamido derivatives as inhibitors of Ras prenylation
Kelly, Joseph,Wolin, Ronald,Connolly, Michael,Afonso, Adriano,James, Linda,Kirshmeier, Paul,Bishop, W. Robert,McPhail, Andrew T.
, p. 673 - 686 (2007/10/03)
Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of nonsulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras. Copyright (C) 1998 Elsevier Science Ltd.
