New bivalent PKC ligands linked by a carbon spacer: Enhancement in binding affinity

Jayalakshmi Sridhar, Zhi Liang Wei, Ireneusz Nowak, Nancy E. Lewin, Jolene A. Ayres, Larry V. Pearce, Peter M. Blumberg, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

Protein kinase C (PKC) is known to play an important role in many signal transduction pathways involved in hormone release, mitogenesis, and tumor promotion. In continuation of our efforts to find highly potent activators of PKC for possible use as Alzheimer's disease therapeutics, we designed and synthesized molecules containing two binding moieties (amides of benzolactams or esters of naphthylpyrrolidones) connected by a flexible spacer chain, which could theoretically bind to both the C1a and C1b activator binding domains of the catalytic region or to the C1 domains of two adjacent PKC molecules. The dimers 2a-g of benzolactam showed a 200-fold increase in affinity to PKCα and -δ as the spacer length increased from 4 to 20 carbon atoms. Replacement of the oligomethylene chain with an oligoethylene glycol unit (compounds 2h, 2i) showed a 4000- to 7000-fold decrease in affinity to PKCα. The dimers of naphthylpyrrolidones 4a-g did not show any marked improvement in binding affinities to PKC in comparison to the monomers synthesized earlier. The dimer of benzolactam 2e did not show much selectivity for PKCα, -βI, -δ, -ε, and -γ. The high binding affinity of compounds 2d-g to PKCs gives us the impetus to design additional molecules that would retain this enhanced activity and would also show selectivity for the PKC isoforms.

Original languageEnglish (US)
Pages (from-to)4196-4204
Number of pages9
JournalJournal of Medicinal Chemistry
Volume46
Issue number19
DOIs
StatePublished - Sep 11 2003
Externally publishedYes

Fingerprint

Protein Kinase C
Carbon
Ligands
Dimers
Molecules
Signal transduction
Glycols
Amides
Tumors
Signal Transduction
Catalytic Domain
Alzheimer Disease
Protein Isoforms
Esters
Monomers
Hormones
Atoms
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sridhar, J., Wei, Z. L., Nowak, I., Lewin, N. E., Ayres, J. A., Pearce, L. V., ... Kozikowski, A. P. (2003). New bivalent PKC ligands linked by a carbon spacer: Enhancement in binding affinity. Journal of Medicinal Chemistry, 46(19), 4196-4204. https://doi.org/10.1021/jm0302041

New bivalent PKC ligands linked by a carbon spacer : Enhancement in binding affinity. / Sridhar, Jayalakshmi; Wei, Zhi Liang; Nowak, Ireneusz; Lewin, Nancy E.; Ayres, Jolene A.; Pearce, Larry V.; Blumberg, Peter M.; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 46, No. 19, 11.09.2003, p. 4196-4204.

Research output: Contribution to journalArticle

Sridhar, J, Wei, ZL, Nowak, I, Lewin, NE, Ayres, JA, Pearce, LV, Blumberg, PM & Kozikowski, AP 2003, 'New bivalent PKC ligands linked by a carbon spacer: Enhancement in binding affinity', Journal of Medicinal Chemistry, vol. 46, no. 19, pp. 4196-4204. https://doi.org/10.1021/jm0302041
Sridhar J, Wei ZL, Nowak I, Lewin NE, Ayres JA, Pearce LV et al. New bivalent PKC ligands linked by a carbon spacer: Enhancement in binding affinity. Journal of Medicinal Chemistry. 2003 Sep 11;46(19):4196-4204. https://doi.org/10.1021/jm0302041
Sridhar, Jayalakshmi ; Wei, Zhi Liang ; Nowak, Ireneusz ; Lewin, Nancy E. ; Ayres, Jolene A. ; Pearce, Larry V. ; Blumberg, Peter M. ; Kozikowski, Alan P. / New bivalent PKC ligands linked by a carbon spacer : Enhancement in binding affinity. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 19. pp. 4196-4204.
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