Structure-activity studies on the side chain of a simplified analog of aplysiatoxin (aplog-1) with anti-proliferative activity.

We have recently developed a simplified analog of aplysiatoxin (aplog-1) as an activator of protein kinase C (PKC) with anti-proliferative activity like bryostain 1. To identify sites in aplog-1 that could be readily modified to optimize therapeutic performance and to develop a molecular probe for examining the analog's mode of action, substituent effects on the phenol ring were systematically examined. Whereas hydrophilic acetamido derivatives were less active than aplog-1 in inhibiting cancer cell growth and binding to PKCĪ“, introduction of hydrophobic bromine and iodine atoms enhanced both biological activities. The anti-proliferative activity was found to correlate closely with molecular hydrophobicity, and maximal activity was observed at a logP value of 4.0-4.5. On the other hand, an induction test with Epstein-Barr virus early antigen demonstrated that these derivatives have less tumor-promoting activity in vitro than aplog-1 regardless of the hydrophobicity of their substituents. These results would facilitate rapid preparation of molecular probes to examine the mechanism of the unique biological activities of aplog-1.
AuthorsHiroaki Kamachi, Keisuke Tanaka, Ryo C Yanagita, Akira Murakami, Kazuma Murakami, Harukuni Tokuda, Nobutaka Suzuki, Yu Nakagawa, Kazuhiro Irie
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 10 Pg. 2695-702 (May 15 2013) ISSN: 1464-3391 [Electronic] England
PMID23582444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Lyngbya Toxins
  • aplysiatoxin
  • Protein Kinase C
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Humans
  • Lyngbya Toxins (chemistry, pharmacology)
  • Protein Kinase C (metabolism)
  • Structure-Activity Relationship

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