Seco-cyclic phorbol derivatives and their anti-HIV-1 activities  

作　　者：HUANG Xiaolei HUANG Xusheng LI Qirun MA Mengdi CUI Yadong YANG Liumeng WANG Haibo LUO Ronghua CHEN Jinglei YANG Jingxuan LIN Jinrong LI Duxin ZHENG Yongtang ZHANG Jian 

机构地区：[1]College of Pharmaceutical Science,Soochow University,Suzhou 215123,China [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [3]Kunming College of Life Science,University of Chinese Academy of Sciences,Kunming 650204,China [4]College of Traditional Chinese Medicine,Yunnan University of Chinese Medicine,Kunming 650500,China

出　　处：《Chinese Journal of Natural Medicines》2024年第4期365-374,共10页中国天然药物（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81202882 and 82060670);the Suzhou Science and Technology Planning Project in Jiangsu Province of China(No.SNG2021022);the Priority Academic Program Development of the Jiangsu Higher Education Institutes,China(PAPD);Project of Innovative Research Team of Yunnan Province(No.202005AE160005)。

摘　　要：Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C(PKC).The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20,C3/C4,and C9 of phorbol.Concurrently,the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex.The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration.This research entailed the hydrolysis of phorbol,producing seco-cyclic phorbol derivatives.The anti-HIV-1 efficacy of these derivatives was assessed,and the affinity constant(Kd)for PKC-δprotein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry.The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity.Remarkably,compound S11,with an EC_(50) of 0.27μmol·L^(−1) and a CC_(50) of 153.92μmol·L^(−1),demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription(ssDNA and 2LTR),likely acting at the viral entry stage,yet showed no affinity for the PKC-δprotein.These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

关 键 词：seco-Cyclic phorbol derivatives Hydrolysis reaction Cyclopropane ring ESTERIFICATION Anti-HIV-1 agent 

分 类 号：R284.2[医药卫生—中药学] R965[医药卫生—中医学]