Rong Sheng

Zhejiang University, Hang-hsien, Zhejiang Sheng, China

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Publications (40)88.32 Total impact

  • Shan Li · Lingfei Wang · Yongzhou Hu · Rong Sheng
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    ABSTRACT: Autophagy is an important basic metabolic mechanism by engulfing and degrading the unnecessary or dysfunctional cellular components within double-membered autolysosomes to maintain cellular homeostasis. Autophagy has sparkled great interest for its complicated functions in different stages of cancer, and is regarded as a potential target for anticancer therapy. As a suppressor pathway, autophagy prevents tumor initiation and as a survival pathway, autophagy contributes to tumor growth and progression by attenuating cellular metabolic stress and resisting therapeutic agents-induced cell death. Many autophagy regulators have been identified as potential cancer therapeutic agents and some cytotoxic anticancer drugs also induce autophagy. Combination regimen of autophagy regulators with other anticancer agent exhibits desirable efficacy and several protocols are underway in clinical trials. This review delineates the possible role of autophagy in anticancer therapy, and discusses reported potent autophagy regulators in cancer treatment.
    Current Topics in Medicinal Chemistry 03/2015; 15(8). DOI:10.2174/1568026615666150302105343 · 3.40 Impact Factor
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    ABSTRACT: A series of novel 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazoline derivatives (15a-15r) were designed, synthesized and evaluated as efficient EGFR inhibitors through introduction of hypoxia activated nitroimidazole moiety into the quinazoline scaffold of EGFR inhibitors. The majority of these newly synthesized compounds exhibited comparable EGFR inhibitory activities to gefitinib and moderate to excellent anti-proliferative activities against HT-29 cells under normoxia and hypoxia. The most promising compound 15c displayed the IC50 value of 0.47 nM against EGFR kinase and excellent cytotoxic effect against HT-29 cells under normoxia and hypoxia with the IC50 values of 2.21 μM and 1.62 μM, respectively. The mimic reductive activation study revealed that compound 15c exerted reductive activation properties under hypoxia, which were consistent with the in vitro metabolic study, wherein 15c was easily reductive activated under hypoxia and much more stable under normoxia. All these results suggested that 15c was a potential cancer therapeutic agent both under normoxia and hypoxia and was worth of further development. Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medicinal Chemistry 11/2014; 89C:826-834. DOI:10.1016/j.ejmech.2014.11.010 · 3.45 Impact Factor
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    ABSTRACT: A novel series of 4-anilinoquinazoline derivatives (19a–19t) were designed and synthesized through incorporation of the 2-nitroimidazole moiety into the 4-anilinoquinazoline scaffold of EGFR inhibitors. The most promising compound 19h displayed potent EGFR inhibitory activity with the IC50 value of 0.47 nM. It also strongly suppressed the proliferation of A549 and HT-29 cells with sub-micromolar IC50 values both under normoxia and hypoxia, which were several folds more potent than gefitinib and erlotinib. Further reductive mimic investigation revealed that 19h could be reductive activated under hypoxia and was fully consistent with the results of cell apoptotic assay and in vitro metabolism evaluation. Our results suggest that the incorporation of hypoxia-activated moiety into EGFR inhibitor scaffold might be a tractable strategy to overcome the tumor hypoxia.
    Bioorganic & Medicinal Chemistry 11/2014; 22(24). DOI:10.1016/j.bmc.2014.10.038 · 2.79 Impact Factor
  • Weiyan Cheng · Yongzhou Hu · Rong Sheng
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    ABSTRACT: The epidermal growth factor receptor (EGFR) family includes four structurally related receptor tyrosine kinases, HER1 (EGFR, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4).Given its intimate role in the development of several solid tumors, excessive HER signaling provides a unique opportunity for anticancer intervention. Along with extensive pharmacological studies validating the therapeutic potential of targeting the EGFR family for cancer therapy, kinase inhibitors of this family keep arising and entering clinical studies. Herein, we review the EGFR family small molecular kinase inhibitors which have been approved or progressed into clinical studies, focusing our attention on their medicinal chemistry in terms of chemical structure, synthetic route, mechanisms of action, structure-activity relationships, binding modes and clinical development.
    Current Medicinal Chemistry 09/2014; 21(38). DOI:10.2174/0929867321666140915142809 · 3.85 Impact Factor
  • Yujie Li · Peng Peng · Li Tang · Yunzhen Hu · Yongzhou Hu · Rong Sheng
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    ABSTRACT: A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097 mu M, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against A beta self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS(center dot+) scavenging and moderate copper ion chelating activity in vitro.
    Bioorganic & Medicinal Chemistry 09/2014; 22(17). DOI:10.1016/j.bmc.2014.07.009 · 2.79 Impact Factor
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    ABSTRACT: 2-phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function wouldn't affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40μM-54μM. And we suggested that 5,6-Dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp.
    International Journal of Pharmaceutics 11/2013; 460(1). DOI:10.1016/j.ijpharm.2013.11.013 · 3.65 Impact Factor
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    ABSTRACT: A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.
    Bioorganic & medicinal chemistry 08/2013; 21(19). DOI:10.1016/j.bmc.2013.07.051 · 2.79 Impact Factor
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    Lushan Yu · Yan Jiang · Lu Wang · Rong Sheng · Yongzhou Hu · Su Zeng
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    ABSTRACT: BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one], belongs to a series of novel acetylcholinesterase inhibitors and has been synthesized as a new chemical entity for the treatment of Alzheimer's disease symptoms. When incubated with human liver microsomes (HLMs), BYZX was rapidly transformed into its metabolites M1, M2, and M3. The chemical structures of these metabolites were identified using liquid chromatography tandem mass spectrometry and nuclear magnetic resonance, which indicated that M1 was an N-desethylated and C = C hydrogenation metabolite of BYZX. M2 and M3 were 2 precursor metabolites, which resulted from the hydrogenation and desethylation of BYZX, respectively. Further studies with chemical inhibitors and human recombinant cytochrome P450s (CYPs), and correlation studies were performed. The results indicated that the N-desethylation of BYZX and M2 was mediated by CYP3A4 and CYP2C8. The reduced form of β-nicotinamide adenine dinucleotide 2'-phosphate was involved in the hydrogenation of BYZX and M3, and this reaction occurred in the HLMs and in the human liver cytosol. The hydrogenation reaction was not inhibited by any chemical inhibitors of CYPs, but it was significantly inhibited by some substrates of α,β-ketoalkene C = C reductases and their inhibitors such as benzylideneacetone, dicoumarol, and indomethacin. Our results suggest that α,β-ketoalkene C = C reductases may play a role in the hydrogenation reaction, but this issue requires further clarification.
    PLoS ONE 03/2013; 8(3):e59882. DOI:10.1371/journal.pone.0059882 · 3.23 Impact Factor
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    ABSTRACT: Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.
    Molecules 03/2013; 18(3):3577-94. DOI:10.3390/molecules18033577 · 2.42 Impact Factor
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    Rong Sheng · Jiangwei Zhu · Yongzhou Hu
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    ABSTRACT: The Winterfeldt oxidation (NaOH, DMF, air, rt) of substituted 1,2,3,4-tetrahydro-γ-carbolines has been developed, which provides a convenient and efficient method for the synthesis of the corresponding dihydropyrrolo[3,2-b]quinolones in moderate to excellent yields (38-94%). The generality and substrate scope of this reaction are explored and a possible mechanism is proposed. The results imply that electron-withdrawing groups on N2 of tetrahydro-γ-carbolines and N5-H are necessary. The synthesis of 5 or 7-substituted pyrrolo[3,2-b]quinolones in near quantitative yields was also achieved through deprotection and aromatization of N1-Boc-dihydropyrrolo[3,2-b]quinolones.
    Molecules 12/2012; 17(2):1177-90. DOI:10.3390/molecules17021177 · 2.42 Impact Factor
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    ABSTRACT: A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC₅₀ values ranging from 0.31 to 3.16 μM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway.
    Molecules 12/2012; 17(8):9683-96. DOI:10.3390/molecules17089683 · 2.42 Impact Factor
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    ABSTRACT: [This corrects the article on p. e42185 in vol. 7.].
    PLoS ONE 08/2012; 7(8). DOI:10.1371/annotation/c536426a-169e-4d9a-8382-cdda0378aa29 · 3.23 Impact Factor
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    ABSTRACT: The histamine H3 receptor (H3R) has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine) and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine) at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.
    PLoS ONE 08/2012; 7(8):e42185. DOI:10.1371/journal.pone.0042185 · 3.23 Impact Factor
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    ABSTRACT: Cumulative evidence has established that hypoxia-inducible factor-1α (HIF-1α) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in hepatocellular carcinoma angiogenesis, invasiveness and metastasis. 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39) has recently shown great antiproliferative activity in extensive cell lines in normoxia and hypoxia. In this study, Q39 exhibited high antiproliferative activity against hepatoma both in vitro and in vivo, mainly by inducing apoptosis. In addition, suppression of HIF-1α by Q39 resulted in a drastic decrease in VEGF expression. These results indicate that Q39 is an effective inhibitor of HIF-1α and provide new perspectives into the mechanism of its anticancer activity. Interestingly, neither the HIF-1α degradation rate nor the HIF-1α steady-state mRNA level was affected by Q39. Instead, suppression of HIF-1α accumulation by Q39 correlated with prominent dephosphorylation of mTOR and 4E-BP1, a pathway known to regulate protein expression at the translational level.
    Investigational New Drugs 12/2011; 29(6):1177-87. DOI:10.1007/s10637-010-9462-y · 2.92 Impact Factor
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    ABSTRACT: A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.
    Bioorganic & medicinal chemistry 12/2011; 19(23):7158-67. DOI:10.1016/j.bmc.2011.09.061 · 2.79 Impact Factor
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    ABSTRACT: Three series of novel imidazoline derivatives were designed, synthesized, and evaluated for their p53–MDM2 binding inhibitory activities, and anti-proliferation activities against PC3, A549, KB, and HCT116 cancer cell lines. Five of the tested compounds showed enhanced p53–MDM2 binding inhibitory potency and anti-proliferation activities in comparison with that of Nutlin-1. Flow cytometric analysis indicated that compound 7c, one of the most potent p53–MDM2 binding inhibitors with a Ki value of 0.6μM, showed its ability to arrest cell cycle progression.
    Bioorganic & medicinal chemistry 09/2011; 19(18):5454-5461. DOI:10.1016/j.bmc.2011.07.050 · 2.79 Impact Factor
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    Journal of chromatographic science 03/2011; 49(3):255-258. DOI:10.1093/chrsci/49.3.255 · 1.36 Impact Factor
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    ABSTRACT: We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC-3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive correlation between hypoxic activity and lipophilicity within a certain range. Preliminary mechanism study on the potent derivatives 4b, 4l and 4m indicated that the cytotoxic activities of these compounds might be mediated by inducing apoptosis.
    European Journal of Medicinal Chemistry 03/2011; 46(3):919-26. DOI:10.1016/j.ejmech.2011.01.007 · 3.45 Impact Factor
  • Rong Sheng · Yongzhou Hu
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    ABSTRACT: A novel and efficient method was developed to synthesize N‐benzyl‐4‐formyl‐piperidine, a key intermediate of Donepezil (Aricept). N‐Benzyl‐4‐piperidone was reacted with dimethyloxosulfonium methylide to get epoxide, followed by rearrangement in the presence of magnesium bromide etherate to give target compound in high yield.
    Synthetic Communications 01/2011; 34(19):3529-3533. DOI:10.1081/SCC-200030987 · 0.93 Impact Factor
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    ABSTRACT: Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a-d, 9a-g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85+/-2.46 micromol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.
    Bioorganic & medicinal chemistry 08/2010; 18(15):5610-5. DOI:10.1016/j.bmc.2010.06.042 · 2.79 Impact Factor

Publication Stats

318 Citations
88.32 Total Impact Points


  • 2003–2014
    • Zhejiang University
      • College of Pharmaceutical Sciences
      Hang-hsien, Zhejiang Sheng, China