Synthesis of a simplified bryostatin C-ring analogue that binds to the CRD2 of human PKC-alpha and construction of a novel BC-analogue by an unusual Julia olefination process.
[structure: see text] The synthesis of two truncated bryostatin analogues 2 and 3 is described. High-field NMR measurements on the C-ring analogue 3 in C(2)H(3)CN containing 25% (2)H(2)O have shown that it binds to the CRD2 of human PKC-alpha at virtually the same position as phorbol-13-acetate (PA) and bryostatin 1 (1). NMR titration studies have also revealed that 3 binds to the CRD2 with a potency similar in magnitude to PA but much less potently than 1.
Hale
Karl J
KJ
The Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, England. k.j.hale@ucl.ac.uk
Frigerio
Mark
M
Manaviazar
Soraya
S
Hummersone
Marc G
MG
Fillingham
Ian J
IJ
Barsukov
Igor G
IG
Damblon
Christian F
CF
Gescher
Andreas
A
Roberts
Gordon C K
GC
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D054713:Bryostatins; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D018942:Macrolides; D019906:Nuclear Magnetic Resonance, Biomolecular; D010703:Phorbol Esters; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D013329:Structure-Activity Relationship; D017186:Titrimetry
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D010703:Phorbol Esters; C050164:phorbol 13-monoacetate; C046785:bryostatin 1; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha