Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators.
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).
Lee
Jeewoo
J
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. jeewoo@snu.ac.kr
Kang
Ji-Hye
JH
Han
Kee-Chung
KC
Kim
Yerim
Y
Kim
Su Yeon
SY
Youn
Hae-Suk
HS
Mook-Jung
Inhee
I
Kim
Hee
H
Lo Han
Jee Hye
JH
Ha
Hee Jin
HJ
Kim
Young Ho
YH
Marquez
Victor E
VE
Lewin
Nancy E
NE
Pearce
Larry V
LV
Lundberg
Daniel J
DJ
Blumberg
Peter M
PM
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D045744:Cell Line, Tumor; D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004075:Diglycerides; D020536:Enzyme Activators; D007783:Lactones; D008024:Ligands; D015240:Phorbol 12,13-Dibutyrate; D051571:Protein Kinase C-alpha; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human