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

作者：Kedei Noemi; Kraft Matthew B; Keck Gary E; Herald Cherry L; Melody Noeleen; Pettit George R; Blumberg Peter M^*

来源：Journal of Natural Products, 2015, 78(4): 896-900.

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.

• 出版日期2015-4