Lee Jeewoo, Kang Ji-Hye, Han Kee-Chung, Kim Yerim, Kim Su Yeon, Youn Hae-Suk, Mook-Jung Inhee, Kim Hee, Lo Han Jee Hye, Ha Hee Jin, Kim Young Ho, Marquez Victor E, Lewin Nancy E, Pearce Larry V, Lundberg Daniel J, Blumberg Peter M
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy and Department of Biochemistry & Cancer Research Institute, Seoul National University, Seoul 151-742, Korea.
J Med Chem. 2006 Mar 23;49(6):2028-36. doi: 10.1021/jm0509391.
Using as our lead structure a potent PKC ligand (1) that we had previously described, we investigated a series of branched DAG-lactones to optimize the scaffold for PKC binding affinity and reduced lipophilicity, and we examined the potential utility of select compounds as alpha-secretase activators. Activation of alpha-secretase upon PKC stimulation by ligands causes increased degradation of the amyloid precursor protein (APP), resulting in enhanced secretion of sAPPalpha and reduced deposition of beta-amyloid peptide (Abeta), which is implicated in the pathogenesis of Alzheimer's disease. We modified in a systematic manner the C5-acyl group, the 3-alkylidene, and the lactone ring in 1 and established structure-activity relationships for this series of potent PKC ligands. Select DAG-lactones with high binding affinities for PKC were evaluated for their abilities to lead to increased sAPPalpha secretion as a result of alpha-secretase activation. The DAG-lactones potently induced alpha-secretase activation, and their potencies correlated with the corresponding PKC binding affinities and lipophilicities. Further investigation indicated that 2 exhibited a modestly higher level of sAPPalpha secretion than did phorbol 12,13-dibutyrate (PDBu).
我们以之前描述过的一种有效的蛋白激酶C（PKC）配体（1）作为先导结构，研究了一系列支链二酰甘油内酯，以优化其与PKC结合亲和力的支架并降低亲脂性，我们还研究了所选化合物作为α-分泌酶激活剂的潜在效用。配体在PKC刺激下激活α-分泌酶会导致淀粉样前体蛋白（APP）的降解增加，从而导致sAPPα分泌增加，β-淀粉样肽（Aβ）沉积减少，而Aβ与阿尔茨海默病的发病机制有关。我们系统地修饰了1中的C5-酰基、3-亚烷基和内酯环，并建立了这一系列有效PKC配体的构效关系。评估了对PKC具有高结合亲和力的所选二酰甘油内酯因α-分泌酶激活而导致sAPPα分泌增加的能力。二酰甘油内酯有效诱导α-分泌酶激活，其效力与相应的PKC结合亲和力和亲脂性相关。进一步研究表明，与佛波醇12,13-二丁酸酯（PDBu）相比，2表现出略高水平的sAPPα分泌。
