Identification of a tunable site in bryostatin analogs: C20 Bryologs through late stage diversification.
[structure: see text] The C20 region of our bryostatin analogs was identified as a nonpharmacophoric site that could be varied to tune analogs for function and physical properties without significantly affecting their binding affinity for PKC. The use of this site in a late-stage diversification strategy has enabled the facile synthesis of a variety of new C20 analogs, all of which retain nanomolar affinity for PKC, in agreement with our pharmacophore hypothesis.
Wender
Paul A
PA
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. wenderp@stanford.edu
Baryza
Jeremy L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D001921:Brain / Q000201:enzymology; D054713:Bryostatins; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D054713:Bryostatins; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C