Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C

Alan P. Kozikowski, Dawei Ma, Yuan-Ping Pang, Patrick Shum, Vladimir Likic, Prasanna K. Mishra, Slobodan I Macura, Alakananda Basu, John S. Lazo, Richard G. Ball

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

To study the structural determinants required for protein kinase C (PKC) activation by indolactam V (ILV) for purposes of arriving at simpler versions of this PKC activator, four simplified analogues of ILV (4a-c and 14a) were synthesized. These analogues contain a benzene ring in place of the indole group of ILV and were designed for synthesis because molecular modeling studies revealed these simplified structures to possess readily accessible [ILV]-sofa-like conformations, thus mimicking the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational search program (SysSearch) was developed to analyze the highly functionalized nine-membered lactam ring system present in ILV. The results of the molecular modeling studies using the SysSearch program on which the design of these analogues was based were confirmed by 2-D NMR and X-ray studies. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam ring present in these structures. Two routes to compound 4a are presented, one of which utilizes the amino acid building blocks, L-valine and L-phenylalanine, to fix the stereochemistry of its two asymmetric centers. The biological studies reveal that these new analogues fail to modulate PKC activity, and thus they exclude the possibility that a benzene ring can serve as a surrogate of the indole ring of ILV. The present work therefore indicates that the nine-membered lactam ring moiety of ILV in an [ILV]sofa conformation is not a sufficient structural determinant for PKC activation.

Original languageEnglish (US)
Pages (from-to)3957-3965
Number of pages9
JournalJournal of the American Chemical Society
Volume115
Issue number10
StatePublished - May 19 1993

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Molecular modeling
Protein Kinase C
Modulators
Nuclear magnetic resonance
Proteins
Conformations
Lactams
Benzene
Chemical activation
Stereochemistry
Amino acids
X rays
indolactam V
Valine
Phenylalanine
X-Rays
Amino Acids

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C. / Kozikowski, Alan P.; Ma, Dawei; Pang, Yuan-Ping; Shum, Patrick; Likic, Vladimir; Mishra, Prasanna K.; Macura, Slobodan I; Basu, Alakananda; Lazo, John S.; Ball, Richard G.

In: Journal of the American Chemical Society, Vol. 115, No. 10, 19.05.1993, p. 3957-3965.

Research output: Contribution to journalArticle

Kozikowski, AP, Ma, D, Pang, Y-P, Shum, P, Likic, V, Mishra, PK, Macura, SI, Basu, A, Lazo, JS & Ball, RG 1993, 'Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C', Journal of the American Chemical Society, vol. 115, no. 10, pp. 3957-3965.
Kozikowski, Alan P. ; Ma, Dawei ; Pang, Yuan-Ping ; Shum, Patrick ; Likic, Vladimir ; Mishra, Prasanna K. ; Macura, Slobodan I ; Basu, Alakananda ; Lazo, John S. ; Ball, Richard G. / Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C. In: Journal of the American Chemical Society. 1993 ; Vol. 115, No. 10. pp. 3957-3965.
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