College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
Bioorg Med Chem Lett. 2021 Oct 15;50:128319. doi: 10.1016/j.bmcl.2021.128319. Epub 2021 Aug 14.
Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.
丁香烷酯类化合物具有多种生物活性，包括抗 HIV-1 活性。本研究旨在建立四个系列丁香烷型二萜类化合物的结构-抗 HIV 活性关系。我们合成并评估了 29 种新型佛波醇酯衍生物的抗 HIV 活性和对人肿瘤细胞系的细胞毒性。其中，三个衍生物，两种佛波醇-13-单酯（5d 和 5e）和一种佛波醇-12,13-二酯（6a）表现出显著的抗 HIV 活性。我们发现，C-13 位较短的酰基酯通常与更好的抗 HIV 活性相关。特别是，酯侧链中含有苯环的化合物表现出优异的抗 HIV 活性，且安全指数良好。由于其显著的抗 HIV 效力和高选择性指数，肉桂酰佛波醇-12,13-二酯（6a）被选为进一步临床前试验的潜在候选药物。
