Synthesis and biological evaluation of the 12,12-dimethyl derivative of Aplog-1, an anti-proliferative analog of tumor-promoting aplysiatoxin.

Abstract

Aplog-1 is a unique analog of tumor-promoting aplysiatoxin that inhibits tumor-promotion by phorbol diesters and proliferation of tumor cells. While the structural features relevant to the biological activities of Aplog-1 remain to be identified, recent studies by us have suggested that local hydrophobicity around the spiroketal moiety of Aplog-1 is a crucial determinant of its anti-proliferative activity. This hypothesis led us to design 12,12-dimethyl-Aplog-1 (3), in which a hydrophobic geminal dimethyl group is installed proximal to the spiroketal moiety to improve biological potency. As expected, 3 was more effective than Aplog-1 in inhibiting cancer cell growth and binding to protein kinase Cδ, a putative receptor responsible for the biological response of Aplog-1. Moreover, an induction test on Epstein-Barr virus early antigen demonstrated 3 to be a better anti-tumor promoter than Aplog-1. These results indicate that 3 is a superior derivative of Aplog-1, and thus a more promising lead for anti-cancer drugs.

• Authors: Yu Nakagawa, Masayuki Kikumori, Ryo C Yanagita, Akira Murakami, Harukuni Tokuda, Hiroshi Nagai, Kazuhiro Irie
• Journal: Bioscience, biotechnology, and biochemistry (Biosci Biotechnol Biochem) Vol. 75 Issue 6 Pg. 1167-73 ( 2011) ISSN: 1347-6947 [Electronic] England
• PMID: 21670518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Antigens, Viral
• Carcinogens
• Epstein-Barr virus early antigen
• Furans
• Lyngbya Toxins
• Phorbol Esters
• Spiro Compounds
• spiroketal
• aplysiatoxin
• Protein Kinase C-delta

Topics

• Anticarcinogenic Agents (chemical synthesis, pharmacology)
• Antigens, Viral (analysis, biosynthesis)
• B-Lymphocytes (pathology, virology)
• Carcinogens (antagonists & inhibitors, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Epstein-Barr Virus Infections (drug therapy, pathology, prevention & control)
• Furans (chemical synthesis, pharmacology)
• Herpesvirus 4, Human (drug effects, physiology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Lyngbya Toxins (adverse effects, pharmacology)
• Methylation
• Neoplasms (drug therapy, pathology, prevention & control)
• Phorbol Esters (adverse effects, pharmacology)
• Protein Binding
• Protein Kinase C-delta (antagonists & inhibitors, metabolism)
• Spiro Compounds (chemical synthesis, pharmacology)
• Structure-Activity Relationship