Synthesis and anti-HIV activities of phorbol derivatives

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE
Xiaolei HUANG , Chengrun TANG , Xusheng HUANG , Yun YANG , Qirun LI , Mengdi MA , Lei ZHAO , Liumeng YANG , Yadong CUI , Zhenqing ZHANG , Yongtang ZHENG , Jian ZHANG
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Abstract

In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c, exhibited the most potent anti-HIV-1 activity (EC50 2.9 nmol·L−1, CC50/EC50 11 117.24) and significantly inhibited the formation of syncytium (EC50 7.0 nmol·L−1, CC50/EC50 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

光稳定剂衍生物的合成与抗艾滋病毒活性
在本研究中,我们在之前合成 51 种植物醇衍生物的基础上,合成了 37 种植物醇酯衍生物,并评估了它们的抗 HIV-1 活性。12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol 衍生物脱颖而出,表现出显著的抗 HIV-1 活性和抑制合胞体形成的作用。与阳性对照药物相比,这些衍生物具有更高的安全性。其中,被命名为化合物 3c 的 12-(反式-4-氟肉桂酰基)-13-癸酰基辛二醇具有最强的抗 HIV-1 活性(EC50 2.9 nmol-L-1,CC50/EC50 117.24),并能显著抑制合胞体的形成(EC50 7.0 nmol-L-1,CC50/EC50 4891.43)。此外,化合物 3c 被认为既是 HIV-1 进入抑制剂,又是 HIV-1 逆转录酶抑制剂。等温滴定量热法和分子对接研究表明,化合物 3c 还可作为蛋白激酶 C (PKC) 的天然激活剂发挥作用。因此,化合物 3c 成为开发新型抗艾滋病毒药物的潜在候选化合物。
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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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