The design, synthesis, and evaluation of C7 diversified bryostatin analogs reveals a hot spot for PKC affinity.
The first series of systematically varied C7-functionalized bryostatin analogs (12 members in all) have been synthesized through an efficient and convergent route. A new hotspot for PKC affinity, not present in the natural products, has been discovered, allowing for affinity control and potentially for selective regulation of PKC isozymes. Several analogs exhibit single-digit nanomolar affinity to PKC and display superior activity compared to bryostatin against the leukemia cell line K562.
Wender
Paul A
PA
Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080, USA. wenderp@stanford.edu
Verma
Vishal A
VA
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054713:Bryostatins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes; D020014:K562 Cells; D008958:Models, Molecular; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D054713:Bryostatins; D007527:Isoenzymes; D011493:Protein Kinase C