| Autor: |
Wender PA; Department of Chemistry, Stanford University, Stanford, California 94305, United States.; Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305, United States., Sloane JL; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Luu-Nguyen QH; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Ogawa Y; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Shimizu AJ; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Ryckbosch SM; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Tyler JH; Department of Chemistry, Stanford University, Stanford, California 94305, United States., Hardman C; Department of Chemistry, Stanford University, Stanford, California 94305, United States. |
| Abstrakt: |
Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin's A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with K i 's < 5 nM, while the latter exhibited PKC affinities that were up to ∼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics in vitro , indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators. |
