Synthesis and biological evaluation of 12-aminoacylphorboids.
Spurred by the paradoxical anti-inflammatory activity of some aminoacylphorbol derivatives, the naturally occurring and epimeric N,N-dimethylvalinoyl-4alpha-4-deoxyphorbol derivatives 3b and 3d have been prepared from 4alpha-4-deoxyphorbol (3e), a byproduct of the isolation of phorbol from Croton oil and a phorboid polyol so far largely overlooked in terms of biological activity. The configuration of the side chain stereocenter was confirmed for both natural products, and to investigate the side chain structure-activity relationships within this class of compounds, their corresponding N,N-dimethylglycinate (3g) and nor (3h) and di-nor derivatives (3i, 3j) were also prepared. By using a PKC-sensitive model of HIV-1 latency (activation of HIV- gene expression in Jurkat-LAT-GFP cells), it was found that both 3b and 3d can activate PKC-dependent responses, while a series of experiments with isoform-specific PKC inhibitors showed that these compounds target PKCalpha and -delta. Both N,N-dimethylation and the presence of side chain alpha-substitution were critical for activity. Selective PKC binding, rather than COX inhibition, might explain the paradoxical anti-inflammatory activity of extracts containing aminoacylphorboids in the mouse ear edema assay.
Pagani
Alberto
A
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita del Piemonte Orientale, Novara, Italy.
Navarrete
Carmen
C
Fiebich
Bernd L
BL
Muñoz
Eduardo
E
Appendino
Giovanni
G
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008954:Models, Biological; D015394:Molecular Structure; D010704:Phorbols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017735:Virus Latency / Q000187:drug effects
D019380:Anti-HIV Agents; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D010704:Phorbols; D020033:Protein Isoforms; D011493:Protein Kinase C