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

• Published in: Journal of natural products (Washington, D.C.) Vol. 78; no. 4; pp. 896 - 900
• Main Authors: Kedei, Noemi, Kraft, Matthew B, Keck, Gary E, Herald, Cherry L, Melody, Noeleen, Pettit, George R, Blumberg, Peter M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 24.04.2015
• Subjects: Animals; bioactive properties; Bryostatins - chemistry; Bryozoa - chemistry; clinical trials; esters; Humans; Models, Molecular; Molecular Structure; neoplasm cells; neoplasms; Neritina; Phorbol Esters; protein kinase C; Protein Kinase C - drug effects; Protein Kinase C - metabolism; structure-activity relationships
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b00094

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.