New bivalent PKC ligands linked by a carbon spacer: enhancement in binding affinity.
New bivalent PKC ligands linked by a carbon spacer: enhancement in binding affinity.
复制标题
由碳间隔基连接的新二价 PKC 配体：增强结合亲和力。
DOI：
10.1021/jm0302041
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Sridhar,Jayalakshmi;Wei,Zhi-Liang;Nowak,Ireneusz;Lewin,NancyE;Ayres,JoleneA;Pearce,LarryV;Blumberg,PeterM;Kozikowski,AlanP
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 dimers2a−gof 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 (compounds2h,2i)showed a 4000- to 7000-fold decrease in affinity to PKCα. The dimers of naphthylpyrrolidones4a−gdid not show any marked improvement in binding affinities to PKC in comparison to the monomers synthesized earlier. The dimer of benzolactam2edid not show much selectivity for PKCα, -βΙ, -δ, -ε, and -γ. The high binding affinity of compounds2d−gto PKCs gives us the impetus to design additional molecules that would retain this enhanced activity and would also show selectivity for the PKC isoforms.
