Sridhar Jayalakshmi, Wei Zhi-Liang, Nowak Ireneusz, Lewin Nancy E, Ayres Jolene A, Pearce Larry V, Blumberg Peter M, Kozikowski Alan P
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3970, Reservoir Road, NW, Washington, D.C. 20057-2197, USA.
J Med Chem. 2003 Sep 11;46(19):4196-204. doi: 10.1021/jm0302041.
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 PKCalpha and -delta 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 PKCalpha. 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 PKCalpha, -betaIota, -delta, -epsilon, and -gamma. 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.
