title: Synthesis and Biological Evaluation of Several Bryostatin Analogues Bearing a Diacylglycerol Lactone C-Ring.
abstract: As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with Ki values of 7000 ± 990 and 4940 ± 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 ± 42 nM. While Merle 46 and 47 were only marginally active biologically, Merle 48 showed sufficient activity on the U937 cells to confirm that it was PMA-like for growth and attachment, as predicted by the substitution pattern of its A- and B-rings.
authors: Department of Chemistry, University of Utah , 315 S 1300 E, RM 2020, Salt Lake City, Utah 84112, United States.
authors: David O
authors: DO
authors: Baumann
authors: Department of Chemistry, University of Utah , 315 S 1300 E, RM 2020, Salt Lake City, Utah 84112, United States.
authors: Kevin M
authors: KM
authors: McGowan
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892-4255, United States.
authors: Noemi
authors: N
authors: Kedei
authors: Basic Science Program, Leidos Biomedical Research, Inc., Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
authors: Megan L
authors: ML
authors: Peach
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892-4255, United States.
authors: Peter M
authors: PM
authors: Blumberg
authors: Department of Chemistry, University of Utah , 315 S 1300 E, RM 2020, Salt Lake City, Utah 84112, United States.
authors: Gary E
authors: GE
authors: Keck
mesh_terms: D054713:Bryostatins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004075:Diglycerides / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D011493:Protein Kinase C / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity
chemical_list: D054713:Bryostatins; D004075:Diglycerides; D007783:Lactones; D011493:Protein Kinase C