Effect of alteration of the heterocyclic nucleus of ILV on its isoform selectivity for PKC. Palladium-catalyzed route to benzofuran analogues of ILV

Alan P. Kozikowski, Dawei Ma, Linh Du, Nancy E. Lewin, Peter M. Blumberg

Research output: Contribution to journalArticle

Abstract

The discovery of isoform-selective modulators of protein kinase C (PKC) appears worthwhile in further defining the roles of the individual PKC isoforms in cell type-specific processes. In comparison with the phorbol esters, little information is available regarding the isoform selectivity of the teleocidin family. Blumberg has reported recently that 7-n-octylindolactam V exhibits little if any selectivity for the isoforms tested. In order to probe the possibility of developing isotype-selective agents based on the indolactam V (ILV) structure, we sought to explore replacement of The indole nucleus by a benzofuran ring. Herein we describe a novel palladium-catalyzed route to four benzofuran analogues 11a-d of ILV together with details of their isoform selectivity. Of considerable interest is the unexpected finding that this subtle N to O structural change leads to a compound (11b) that is modestly more like 12,13-dibutyrate phorbol and less like n-octyl-ILV in its pattern of activity. Moreover, the effect of introducing an additional stereocenter at C-14 into these benzofurans was explored, and a clear preference for R-stereochemistry at the C-14 center of the teleocidin family was found, thus providing additional verification of previously published structural correlations between the families of PKC activators. Overall, the present findings provide an important new direction in the quest for isoform-selective activators of PKC.

Original languageEnglish (US)
Pages (from-to)6666-6672
Number of pages7
JournalJournal of the American Chemical Society
Volume117
Issue number25
DOIs
StatePublished - Jun 28 1995
Externally publishedYes

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Palladium
Protein Kinase C
Protein Isoforms
Proteins
Stereochemistry
Benzofurans
Modulators
Phorbol 12,13-Dibutyrate
Esters
Phorbol Esters
indolactam V
benzofuran

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Effect of alteration of the heterocyclic nucleus of ILV on its isoform selectivity for PKC. Palladium-catalyzed route to benzofuran analogues of ILV. / Kozikowski, Alan P.; Ma, Dawei; Du, Linh; Lewin, Nancy E.; Blumberg, Peter M.

In: Journal of the American Chemical Society, Vol. 117, No. 25, 28.06.1995, p. 6666-6672.

Research output: Contribution to journalArticle

Kozikowski, Alan P. ; Ma, Dawei ; Du, Linh ; Lewin, Nancy E. ; Blumberg, Peter M. / Effect of alteration of the heterocyclic nucleus of ILV on its isoform selectivity for PKC. Palladium-catalyzed route to benzofuran analogues of ILV. In: Journal of the American Chemical Society. 1995 ; Vol. 117, No. 25. pp. 6666-6672.
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