相似的吡啶酮类化合物具有显著不同的抗HIV-1逆转录酶活性（英文）
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摘要
在结构多样的非核苷类逆转录酶抑制剂中,吡啶酮类化合物对于HIV-1野生株病毒和突变株病毒均表现出了良好活性。在对课题组前期的吡啶酮类抑制剂LAM-trans进行结构改造的过程中,我们发现在4位引入氮原子可以显著改善化合物的水溶性,但是结构中哌啶N原子的质子化导致了化合物与结合口袋疏水作用力的减弱。特别的是,质子化改变了脂环在疏水口袋中的取向,进而阻碍了关键卤素键的形成并最终导致抗HIV-1逆转录酶活性的巨大改变。这些研究结果,为以后吡啶酮类化合物的结构改造提供了一定的理论基础和实验依据。
Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1(LAM-trans), we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility(7b), whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.
Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1(LAM-trans), we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility(7b), whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.
引文
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[12]Cao,Y.Y.;Zhang,Y.;Wu,S.T.;Yang,Q.Z.;Sun,X.;Zhao,J.X.;Pei,F.;Guo,Y.;Tian,C.;Zhang,Z.L.;Wang,H.N.;Ma,L.Y.;Liu,J.Y.;Wang,X.W.Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs.Bioorg.Med.Chem.2015,23,149–159.
[13]Qin,H.;Liu,C.;Guo,Y.;Wang,R.P.;Zhang,J.F.;Ma,L.Y.;Zhang,Z.L.;Wang,X.W.;Cui,Y.X.;Liu,J.Y.Synthesis and biological evaluation of novel C5 halogenfunctionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.Bioorg.Med.Chem.2010,18,3231–3237.
[14]Malla,P.;Kumar,R.;Kumar,M.Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling,Atom-Based 3D-QSAR and Docking Studies.Chem.Biol.Drug Des.2013,82,71–80.
[15]Gross,G.;Tardio,J.;Kuhlmann,O.Solubility and stability of dalcetrapib in vehicles and biological media.Int.J.Pharm.2012,437,103–109.
[2]De Clercq,E.The role of non-nucleoside reverse transcriptase inhibitors(NNRTIs)in the therapy of HIV-1 infection.Antiviral Res.1998,38,153–179.
[3]De Bethune,M.P.Non-nucleoside reverse transcriptase inhibitors(NNRTIs),their discovery,development,and use in the treatment of HIV-1 infection:a review of the last 20 years(1989–2009).Antiviral Res.2010,85,75–90.
[4]Zhan,P.;Pannecouque,C.;De Clercq,E.;Liu,X.Y.Anti-HIV Drug Discovery and Development:Current Innovations and Future Trends.J.Med.Chem.,2016,59,2849–2878.
[5]Menendez-Arias,L.Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases.Prog.Nucleic Acid Res.Mol.Biol.2002,71,91–147.
[6]Ren,J.;Stammers,D.K.Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase.Virus Res.2008,134,157–170.
[7]Benjahad,A.;Croisy,M.;Monneret,C.;Bisagni,E.;Mabire,D.;Coupa,S.;Poncelet,A.;Csoka,I.;Guillemont,J.;Meyer,C.;Andries,K.;Pauwels,R.;De Bethune,M.P.;Himmel,D.M.;Das,K.;Arnold,E.;Nguyen,C.H.;Grierson,D.S.4-benzyl and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones:In vitro evaluation of new c-3-amino-substituted and c-5,6-alkyl-substituted analogues against clinically important HIV mutant strains.J.Med.Chem.2005,48,1948–1964.
[8]Vite-Caritin,V.;Mendez-Lucio,O.;Reyes,H.;Cabrera,A.;Chavez,D.;Medina-Franco,J.L.Advances in the development of pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors.RSC Adv.2016,6,2119–2130.
[9]Li,A.M.;Ouyang,Y.B.;Wang,Z.Y.;Cao,Y.Y.;Liu,X.Y.;Ran,L.;Li,C.;Li,L.;Zhang,L.;Qiao,K.;Xu,W.S.;Huang,Y.;Zhang,Z.L.;Tian,C.;Liu,Z.M.;Jiang,S.B.;Shao,Y.M.;Du,Y.S.;Ma,L.Y.;Wang,X.W.;Liu,J.Y.Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs)with High Potency against NNRTI-Resistant HIV-1 Strains.J.Med.Chem.2013,56,2593–2608.
[10]Wu,S.T.;Yin,Q.Q.;Zhao,L.;Fan,N.N.;Tang,X.W.;Zhao,J.X.;Sheng,T.;Guo,Y.;Tian,C.;Zhang,Z.L.;Xu,W.S.;Liu,Z.M.;Jiang,S.B.;Ma,L.Y.;Liu,J.Y.;Wang,X.W.A stereo configuration-activity study of3-iodo-4-(2-methylcycl ohexyloxy)-6-phenethylpyridin-2(2H)-ones as potency inhibitors of HIV-1 variants.Org.Biomol.Chem.2016,14,1413–1420.
[11]Zhan,P.;Chen,X.W.;Li,D.Y.;Fang,Z.J.;De Clercq,E.;Liu,X.Y.HIV-1 NNRTIs:structural diversity,pharmacophore similarity,and implications for drug design.Med.Res.Rev.2013,33,E1–E72.
[12]Cao,Y.Y.;Zhang,Y.;Wu,S.T.;Yang,Q.Z.;Sun,X.;Zhao,J.X.;Pei,F.;Guo,Y.;Tian,C.;Zhang,Z.L.;Wang,H.N.;Ma,L.Y.;Liu,J.Y.;Wang,X.W.Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs.Bioorg.Med.Chem.2015,23,149–159.
[13]Qin,H.;Liu,C.;Guo,Y.;Wang,R.P.;Zhang,J.F.;Ma,L.Y.;Zhang,Z.L.;Wang,X.W.;Cui,Y.X.;Liu,J.Y.Synthesis and biological evaluation of novel C5 halogenfunctionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.Bioorg.Med.Chem.2010,18,3231–3237.
[14]Malla,P.;Kumar,R.;Kumar,M.Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling,Atom-Based 3D-QSAR and Docking Studies.Chem.Biol.Drug Des.2013,82,71–80.
[15]Gross,G.;Tardio,J.;Kuhlmann,O.Solubility and stability of dalcetrapib in vehicles and biological media.Int.J.Pharm.2012,437,103–109.