Synthesis and biological activities of simplified analogs of the natural PKC ligands, bryostatin-1 and aplysiatoxin.

Abstract

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.

• Authors: Kazuhiro Irie, Ryo C Yanagita
• Journal: Chemical record (New York, N.Y.) (Chem Rec) Vol. 14 Issue 2 Pg. 251-67 (Apr 2014) ISSN: 1528-0691 [Electronic] United States
• PMID: 24677503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2014 The Chemical Society of Japan and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Bryostatins
• Isoenzymes
• Ligands
• Lyngbya Toxins
• bryostatin 1
• aplysiatoxin
• Protein Kinase C

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, toxicity)
• Bryostatins (chemical synthesis, pharmacology, toxicity)
• Cell Proliferation (drug effects)
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Ligands
• Lyngbya Toxins (chemical synthesis, pharmacology, toxicity)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship