Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs.
[Structure: see text] The total synthesis and preliminary biological evaluation of the first bryostatin analogs (bryologs) to incorporate B-ring substitution are reported. Asymmetric syntheses of two new polyketide "spacer" domains are described, one exploiting the pseudosymmetry of the C1-C13 region. These fragments are convergently joined to the "recognition" domain through a remarkably versatile macrotransacetalization process. The resulting new analogs exhibit potent nanomolar or picomolar affinity to protein kinase C (PKC), comparable to or better than that found for bryostatin.
Wender
Paul A
PA
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. wenderp@stanford.edu
Horan
Joshua C
JC
Verma
Vishal A
VA
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D054713:Bryostatins; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D054713:Bryostatins; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C