Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure-Function Relationships

Noemi Kedei, Matthew B. Kraft, Gary E. Keck, Cherry L. Herald, Noeleen Melody, George Pettit, Peter M. Blumberg

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain. (Chemical Equation)

Original languageEnglish (US)
Pages (from-to)896-900
Number of pages5
JournalJournal of Natural Products
Volume78
Issue number4
DOIs
StatePublished - Apr 24 2015

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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    Kedei, N., Kraft, M. B., Keck, G. E., Herald, C. L., Melody, N., Pettit, G., & Blumberg, P. M. (2015). Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure-Function Relationships. Journal of Natural Products, 78(4), 896-900. https://doi.org/10.1021/acs.jnatprod.5b00094