Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita del Piemonte Orientale, Novara, Italy.
J Nat Prod. 2010 Mar 26;73(3):447-51. doi: 10.1021/np9006553.
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.
受某些氨酰基佛波醇衍生物具有抗炎活性这一矛盾现象的激发，我们从可从巴豆油中分离佛波醇的副产物 4α-4-去氧佛波醇（3e）和迄今为止在生物活性方面基本被忽视的佛波醇多醇中制备出了天然存在的、对映异构的 N,N-二甲基缬氨酰-4α-4-去氧佛波醇衍生物 3b 和 3d。两种天然产物的侧链立体中心的构型都得到了确认，为了研究该类化合物的侧链结构与活性关系，我们还制备了它们相应的 N,N-二甲基甘氨酸酯（3g）、降（3h）和双降（3i、3j）衍生物。通过使用 HIV-1 潜伏（在 Jurkat-LAT-GFP 细胞中激活 HIV 基因表达）的 PKC 敏感模型，我们发现 3b 和 3d 均可激活 PKC 依赖性反应，而一系列针对同工型特异性 PKC 抑制剂的实验表明，这些化合物靶向 PKCalpha 和 -delta。N,N-二甲基化和侧链 α-取代的存在对活性至关重要。选择性 PKC 结合，而不是 COX 抑制，可能解释了在小鼠耳水肿试验中含有氨酰基佛波醇的提取物具有抗炎活性这一矛盾现象。
