Synthesis of structural analogues of lyngbyatoxin A and their evaluation as activators of protein kinase C.
Syntheses of several new analogues of lyngbyatoxin A from a single common intermediate are described. These compounds bear a carbon chain at the 7-position of the indolactam V (ILV) nucleus which contains either a hydrophilic or a lipophilic group. The effect of these minor structural alterations on the ability of the ILV analogues to activate the enzyme protein kinase C (PKC) was determined by measuring the extent of phosphorylation of calf thymus histone (III-S). Introduction of a hydroxyl group on the C-7 appendage was found to dramatically decrease compound 3's ability to activate PKC. This result is interpreted in terms of the decreased ability of 3 to associate with the membrane bilayer.
Kozikowski
A P
AP
Neurochemistry Research, Mayo Clinic Jacksonville, Florida 32224.
Shum
P W
PW
Basu
A
A
Lazo
J S
JS
D000255:Adenosine Triphosphate / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells / Q000201:enzymology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008235:Lyngbya Toxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008387:Marine Toxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006657:Histones; D008235:Lyngbya Toxins; D008387:Marine Toxins; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; C019457:lyngbyatoxin A