The stereochemical requirement for protein kinase C activation by 3-methyldiglycerides matches that found in naturally occurring tumor promoters aplysiatoxins.
Protein kinase C is stereospecifically activated by sn-1,2-(S)-diglycerides. A second chiral center was introduced into the diglycerides by preparing the 3-methyl derivatives. The activation of protein kinase C was also stereospecific with respect to the new chiral center established at the C3 position of the methylated diglycerides. The stereospecifically of protein kinase C directed towards the C2 and C3 positions of the diglycerides is matched in the analogous C29 and C30 stereocenters of the tumor promoting debromoaplysiatoxins. This finding strengthens the view that the structurally diverse tumor promotors contain the embedded diglyceride-like pharmacophore.
Kong
F
F
Department of Chemistry, Harvard University, Cambridge, MA 02138.
Kishi
Y
Y
Perez-Sala
D
D
Rando
R R
RR
D000818:Animals; D001921:Brain / Q000201:enzymology; D002273:Carcinogens; D004075:Diglycerides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D007202:Indicators and Reagents; D007700:Kinetics; D008235:Lyngbya Toxins / Q000737:chemistry*; D008745:Methylation; D015394:Molecular Structure; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D002273:Carcinogens; D004075:Diglycerides; D007202:Indicators and Reagents; D008235:Lyngbya Toxins; C017179:debromoaplysiatoxin; D011493:Protein Kinase C