Junyi Liu

Publications (18)42.09 Total impact

• Article: Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains.

  Amin Li, Yabo Ouyang, Ziyun Wang, Yuanyuan Cao, Xiangyi Liu, Li Ran, Chao Li, Li Li, Liang Zhang, Kang Qiao, [......], Yang Huang, Zhili Zhang, Chao Tian, Zhenming Liu, Shibo Jiang, Yiming Shao, Yansheng Du, Liying Ma, Xiaowei Wang, Junyi Liu
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  ABSTRACT: Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately, and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75,000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile.
  Journal of Medicinal Chemistry 03/2013; · 4.80 Impact Factor
• Article: Mechanism-based design, synthesis and biological studies of N(5)-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents.

  Zhili Zhang, Chao Tian, Shouxin Zhou, Wei Wang, Ying Guo, Jie Xia, Zhenming Liu, Biao Wang, Xiaowei Wang, Bernard T Golding, Roger J Griff, Yansheng Du, Junyi Liu
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  ABSTRACT: A number of 8-deazatetrahydrofolates bearing electrophilic groups on N(5) were designed and synthesized based on the action mechanism of methionine synthase, and their biological activities were investigated as well. Compounds (11b, 12b and 16) showed the most active against methionine synthase (IC(50): 8.11 μM, 1.73 μM, 1.43 μM). In addition, the cytotoxicity to human tumor cell lines and dihydrofolate reductase (DHFR) inhibition by target compounds were evaluated.
  European journal of medicinal chemistry 10/2012; 58C:228-236. · 3.27 Impact Factor
• Source

  Available from: PubMed Central

  Article: 1-Eth-oxy-methyl-5-methyl-9-phenyl-6,7,8,9-tetra-hydro-1H-pyrimido[4,5-b][1,4]diazepine-2,4(3H,5H)-dione.

  Gong Li, Xiaowei Wang, Zhili Zhang, Junyi Liu
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  ABSTRACT: The title compound, C(17)H(22)N(4)O(3), comprises a 1,4-diazepine ring in a twist-boat conformation fused to a pyrimidine ring. The dihedral angle between the pyrimidine and phenyl rings is 80.8 (1)°. The crystal packing features N-H⋯O and C-H⋯O hydrogen bonds.
  Acta Crystallographica Section E Structure Reports Online 05/2012; 68(Pt 5):o1396. · 0.35 Impact Factor
• Source

  Available from: Yabo Ouyang

  Article: Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile.

  Xiaowei Wang, Jianfang Zhang, Yang Huang, Ruiping Wang, Liang Zhang, Kang Qiao, Li Li, Chang Liu, Yabo Ouyang, Weisi Xu, Zhili Zhang, Liangren Zhang, Yiming Shao, Shibo Jiang, Liying Ma, Junyi Liu
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  ABSTRACT: Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.
  Journal of Medicinal Chemistry 03/2012; 55(5):2242-50. · 4.80 Impact Factor
• Article: Novel synthesis of 8-deaza-5,6,7,8-tetrahydroaminopterin analogues via an aziridine intermediate.

  Shouxin Zhou, Chao Tian, Chao Li, Ying Guo, Xiaowei Wang, Junyi Liu, Zhili Zhang
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  ABSTRACT: An efficient method for the construction of the tetrahydrofolate skeleton is described. Starting from pterin analogues and aromatic amines, 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives and the heterocyclic benzoyl isosteres were synthesized via a novel aziridine intermediate. Following this method, the byproducts of carbon-nitrogen bond hydrogenolysis in traditional synthetic strategy can be completely avoided.
  Molecules 01/2012; 17(5):5604-14. · 2.39 Impact Factor
• Source

  Available from: Yang Huang

  Article: Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors.

  Yang Huang, Xiaowei Wang, Xiaoling Yu, Lin Yuan, Ying Guo, Weisi Xu, Tiejun Liu, Junyi Liu, Yiming Shao, Liying Ma
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  ABSTRACT: The non-nucleoside reverse transcriptase inhibitor (NNRTI), as a major component of the highly active antiretroviral therapy (HAART) to HIV-1 (human immunodeficiency virus type 1) infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity. Therefore, a series of novel compounds, 9-phenylcyclohepta[d]pyrimidinedione derivatives (PCPs), were designed based on the chemical structure of TNK-651, to detect anti-HIV-1 activity. 1-[(benzyloxy)methyl]-9-phenyl-cyclohepta[d] pyrimidinedione (BmPCP) among four PCPs has antiviral activity on laboratory-adapted HIV strains (HIV-1 SF33). The results showed 50% inhibition concentrations (IC50s) of BmPCP were 0.34 μM, 1.72 μM and 1.96 μM on TZM-bl, peripheral blood mononuclear cells (PBMCs) and MT4, respectively. It was also effective against infection by the predominant HIV-1 isolates in China, with IC50s at low μM levels. Its selectivity index (SI) ranged from 67 to 266 in different cells. The results of time-of-addition assay demonstrated that BmPCP inhibited HIV-1 infection by targeting the post entry of the HIV-1 replication cycle. For inhibition of HIV-1 reverse transcriptase activity, the IC50 values of BmPCP and NVP were 1.51 and 3.67 μM, respectively. BmPCP with a novel structure acts as a NNRTI to inhibit HIV-1 replication and can serve as a lead compound for further development of new anti-HIV-1 drugs.
  Virology Journal 01/2011; 8:230. · 2.34 Impact Factor
• Article: Study on the interaction between HIV reverse transcriptase and its non-nucleoside inhibitor nevirapine by capillary electrophoresis.

  Wenjing Chen, Wujie Li, Xiaomei Ling, Xiaowei Wang, Junyi Liu
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  ABSTRACT: The HIV reverse transcriptase (RT) is an important antiviral target for the chemotherapy of AIDS because of its key role in virus replication. Nevirapine is a first generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which is usually used for the therapy of AIDS. In this study, a high-performance analytical method based on capillary electrophoresis (CE) to investigate interactions between HIV RT and nevirapine was developed. Samples containing HIV RT and nevirapine at various ratios were incubated at 37 degrees C for 45 min and then separated by CE with Tris-acetate buffer at pH 7.3 containing 0.15% SDS. Both qualitative and quantitative characterizations of the binding were determined by CE for the first time. The binding constants of the interactions between HIV RT and nevirapine were calculated as (3.25+/-0.16)x10(4) and (1.25+/-0.07)x10(2) M(-1) by Scatchard analysis. HIV RT and nevirapine have two binding sites. The presented methodology should be generally applicable to study the interactions between HIV RT and nevirapine quantitatively and qualitatively.
  Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 06/2010; 878(20):1714-7. · 2.78 Impact Factor
• Article: Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

  Hua Qin, Chang Liu, Ying Guo, Ruiping Wang, Jianfang Zhang, Liying Ma, Zhili Zhang, Xiaowei Wang, Yuxin Cui, Junyi Liu
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  ABSTRACT: A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC(50) values (IC(50) 0.18-3.03 microM) comparable to nevirapine (IC(50) 4.12 microM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.
  Bioorganic & medicinal chemistry 03/2010; 18(9):3231-7. · 2.82 Impact Factor
• Article: Efficient Preparation of Photolabile Agent MNI-glu by Regioselective Nitration of 4-Methoxyindoline Derivative

  Xiaowei Wang, Yu Gao, Yang Xu, Li Li, Zhili Zhang, Junyi Liu
  Synthetic Communications 11/2009; 39(22):4030-4038. · 1.06 Impact Factor
• Article: [Study on pharmacokinetics model for targeted drug delivery systems].

  Lingbing Li, Pei Wei, Junyi Liu
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  ABSTRACT: Multi-compartment linear circulation mathematical model for targeted drug delivery systems was established on the bases of compartment theory and mass conservation theory. The function formulas of drug concentration-time in blood and target organ were established. According to this model, the drug concentration-time curve for the target organ can be plotted with reference to the data on blood. Based on the target organ drug concentration-time curve,the pharmacokinetics parameters of the target organ can also be calculated by the statistical moment. We further detected the practicability of the models by using the experimental data of drug concentration-time curve in blood and target organ of microspheres. The drug concentration-time curve in blood and in target organ predicted by mathematical model was agreed with that observed.
  Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi 07/2009; 26(3):526-9.
• Article: Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

  Hua Qin, Chang Liu, Jianfang Zhang, Ying Guo, Siwei Zhang, Zhili Zhang, Xiaowei Wang, Liangren Zhang, Junyi Liu
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  ABSTRACT: Novel 2-aryalkylthio-4-amino-6-benzylpyrimidines (3a-i), which can be considered as S-DABO and TMC-125 analogue hybrid molecules, have been designed and synthesized as inhibitors of HIV-1 RT. The results clearly indicated that the changes at the N(3)/C(4) position of pyrimidine ring could affect the hydrogen bonds strength and number between N(3)/C(4) and the Lys101 residue which are indispensable for anti-HIV-1 RT activity. The biological activity results are also in accordance with the docking study.
  Bioorganic & medicinal chemistry letters 04/2009; 20(9):3003-5. · 2.65 Impact Factor
• Article: Pyrimidone derivative inhibits simian immunodeficiency virus-induced apoptosis of CEM x174 cells

  Libo Gao, Shigan Fu, Hui Li, Xiaowei Wang, Junyi Liu, Han Liu, Liyuan Guo, Xinhua Liu, Mengsen Li, Michael A. McNutt, Gang Li
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  ABSTRACT: The biochemical effects of 2-(ethoxymethylthio)-9-phenyl-cyclohepta[d]pyrimidone (EPCP), a novel non-nucleoside reverse transcriptase inhibitor, have been investigated. Treatment with EPCP (EC50 of 0.88 nM in CEM x174 cells) significantly inhibited the activity of SIV reverse transcriptase and elevated the percentage of viable cells in an SIV-infected sample in a dose-dependent manner. The percentage of cells accumulated in G1 phase increased significantly from 34.5 to 62.4%, with a concomitant reduction in S-phase from 50.7% in the control to 22.6% in the infected group. This cell cycle profile was restored by treatment with EPCP. SIV upregulated the levels of the caspase-3, p53 and bax proteins, and downregulated the level of bcl-2 in infected cells. The apoptotic effect of SIV was also blocked by treatment with EPCP. The pharmacological effects of EPCP paralleled those of AZT, suggesting the possibility that EPCP might be a novel antiviral agent for SIV.
  Cell Biology International 12/2008; · 1.48 Impact Factor
• Article: Two newly synthesized 5-methyltetrahydrofolate-like compounds inhibit methionine synthase activity accompanied by cell cycle arrest in G1/S phase and apoptosis in vitro.

  Cai Tang, Zhili Zhang, Bo Xu, Min Li, Junyi Liu, Jingrong Cui
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  ABSTRACT: Cobalamin-dependent methionine synthase, with a cofactor of vitamin B12, catalyzes the reaction of 5-methyltetrahydrofolate and homocysteine to form methionine and tetrahydrofolate, which takes a core position in folate cycle, one-carbon-unit transfer, and sulfur amino acid pathways. The 'methyl folate trap' hypothesis suggests that methionine synthase is a potential target for anticancer drug development. ZL031 and ZL033 are 5-methyltetrahydrofolate-like compounds that have been newly synthesized as potential inhibitors of the enzyme. To identify the effect of these two compounds on methionine synthase activity, a spectrophotometric assay was used and the results proved that ZL031 and ZL033 inactivated methionine synthase in HL-60 cells with an IC50 dose of 10.0 and 1.4 mumol/l, respectively. Moreover, obvious inhibitory effect on proliferation of HL-60 cells was observed, leading to our further investigation of the underlying anticancer mechanism. Under the circumstances of methionine synthase deficiency and subsequent folate depletion, cell cycle was arrested in G1/S phase and apoptosis was also observed. Analysis of cell cycle regulatory proteins demonstrated that cyclin E and cyclin-dependent kinase 2 were both increased. Furthermore, reduction of caspase-3, poly (ADP-ribose) polymerase, caspase-8, and caspase-9 protein levels were observed. In all the biological experiments we have performed, ZL033 has shown a better efficacy compared with ZL031. These results suggest that ZL031 and ZL033, as novel methionine synthase inhibitors, caused G1/S phase delay and apoptosis and eventually inhibit the proliferation of HL-60 cells in vitro. ZL033, with a carboxylic acid substituent, might have a better potential for drug development than ZL031 with an ester substituent.
  Anti-Cancer Drugs 09/2008; 19(7):697-704. · 2.41 Impact Factor
• Article: Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: design, synthesis and antifolate activity.

  Zhili Zhang, Jun Wu, Fuxiang Ran, Ying Guo, Ran Tian, Shouxin Zhou, Xiaowei Wang, Zhenming Liu, Liangren Zhang, Jingrong Cui, Junyi Liu
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  ABSTRACT: We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results.
  European journal of medicinal chemistry 06/2008; 44(2):764-71. · 3.27 Impact Factor
• Article: The design and synthesis of N-1-alkylated-5-aminoarylalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors.

  Xiao Lu, Yanli Chen, Ying Guo, Zhenming Liu, Yawei Shi, Yang Xu, Xiaowei Wang, Zhili Zhang, Junyi Liu
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  ABSTRACT: Novel compounds 1a-u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyluracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxymethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a-u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a-u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC(50) values (IC(50) 0.82-5.09 microM) comparable to that of nevirapine (IC(50) 10.60 microM). The biological testing results are in accordance with the docking.
  Bioorganic & Medicinal Chemistry 01/2008; 15(23):7399-407. · 2.92 Impact Factor
• Article: The design and synthesis of 9-phenylcyclohepta[d]pyrimidine-2,4-dione derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase.

  Xiaowei Wang, Qinghua Lou, Ying Guo, Yang Xu, Zhili Zhang, Junyi Liu
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  ABSTRACT: Novel compounds, which can be considered as conformationally restricted analogues of MKC-442, have been synthesized and tested as inhibitors of the reverse transcriptase of human immunodeficiency virus type-1 (HIV-1). Reaction of urea with a beta-ketoester furnished 6,7,8,9-tetrahydro-9-phenyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6a) and 6,7,8,9-tetrahydro-9-p-tolyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6b) which were then alkylated at the N-1 position with chloromethyl ether, allyl bromide and benzyl bromide to afford the target compounds 7a-b, 8a-b, 9 and 10, respectively. The seven-membered, annelated compounds have a relatively rigid structures and can lock the orientation of the aromatic ring. Chemical modification at N-1 of the pyrinidine ring and the 9-phenyl ring was attempted, with the aim of improving the antiretroviral activity. In particular, replacement of the aliphatic group with the phenyl moiety at the terminus of N-1 side chain can enhance the activity. The most active compounds showed activity in the low micromolar range with IC50 values comparable to that of nevirapine. The biological activity results are in accordance with the docking results.
  Organic & Biomolecular Chemistry 10/2006; 4(17):3252-8. · 3.70 Impact Factor
• Article: Synthesis of l‐(Alkoxymethyl)‐5‐benzyl‐6‐methyluracil as Potential Nonnucleoside HIV‐1 RT Inhibitors

  Yanli Chen, Ying Guo, Hua Yang, Xiaowei Wang, Junyi Liu
  Synthetic Communications 01/2006; 36(19):2913-2920. · 1.06 Impact Factor
• Article: The design and synthesis of N-1-alkylated-5-aminoaryalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors

  Xiao Lu, Yanli Chen, Ying Guo, Zhenming Liu, Yawei Shi, Yang Xu, Xiaowei Wang, Zhili Zhang, Junyi Liu
  Bioorganic & Medicinal Chemistry. 15(23):7399-7407.