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

14 Citations (Scopus)

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

Fingerprint

Protein Kinase C
Phorbol Esters
Activator Appliances
neristatin 1
bryostatin 1
Lactones
Bioactivity
Carrier Proteins
Leukemia
Clinical Trials
Molecules
Neoplasms

ASJC Scopus subject areas

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

Cite this

Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure-Function Relationships. / Kedei, Noemi; Kraft, Matthew B.; Keck, Gary E.; Herald, Cherry L.; Melody, Noeleen; Pettit, George; Blumberg, Peter M.

In: Journal of Natural Products, Vol. 78, No. 4, 24.04.2015, p. 896-900.

Research output: Contribution to journalArticle

Kedei, Noemi ; Kraft, Matthew B. ; Keck, Gary E. ; Herald, Cherry L. ; Melody, Noeleen ; Pettit, George ; Blumberg, Peter M. / Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure-Function Relationships. In: Journal of Natural Products. 2015 ; Vol. 78, No. 4. pp. 896-900.
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