Synthesis of structural analogs of lyngbyatoxin A and their evaluation as activators of protein kinase C

• Published in: Journal of medicinal chemistry Vol. 34; no. 8; pp. 2420 - 2430
• Main Authors: Kozikowski, Alan P, Shum, Patrick W, Basu, Alakananda, Lazo, John S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1991
• Subjects: Adenosine Triphosphate - metabolism; Chemical Phenomena; Chemistry; Enzyme Activation - drug effects; Exact sciences and technology; HeLa Cells - enzymology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Histones - metabolism; Humans; Lyngbya Toxins - chemical synthesis; Lyngbya Toxins - chemistry; Lyngbya Toxins - pharmacology; Marine Toxins - chemical synthesis; Marine Toxins - chemistry; Marine Toxins - pharmacology; Molecular Structure; Organic chemistry; Phosphorylation; Preparations and properties; protein kinase C; Protein Kinase C - metabolism; Structure-Activity Relationship; Protein kinase C; Enzyme; Activator; Nitrogen heterocycle; Lactam; Aromatic compound; Tricyclic compound; Biological activity; Primary alcohol
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00112a017

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.