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ABSTRACT: A series of graveoline and graveolinine derivatives were synthesized. The biological results showed that most of graveoline derivatives possessed higher cytotoxicity and better inhibitive effect against the adhesion and migration of human umbilical vein endothelial cell (HUVEC) than graveolinine derivatives. Among these compounds, 8d was the most potent agents that also showed significant anti-angiogenesis activities in chick embryo chorioallantoic membrane (CAM) assay.
European journal of medicinal chemistry 09/2010; 45(9):3895-903. · 3.27 Impact Factor
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Bin Wang,
Wen-Yi Chu,
Zeng Li,
Jin-Qiang Hou,
Shi-Liang Huang,
Tian-Miao Ou,
Jia-Heng Tan,
Lin-Kun An,
Ding Li, Lian-Quan Gu,
Zhi-Shu Huang
Rapid Communications in Mass Spectrometry 09/2010; 24(18):2781-6. · 2.79 Impact Factor
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ABSTRACT: A series of novel indolizinophthalazine-5,12-dione derivatives were designed and synthesized by the reaction of 6,7-dichlorophthalazine-5,8-dione with active methylene reagents (AMR) and pyridine derivatives. Some of synthesized compounds exhibited significant in vitro antiproliferative activity at micromolar level toward four human tumor cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell and ardriamycin-resistance breast carcinoma cell. The DNA topoisomerase IB inhibitory assay indicated that DNA topoisomerase IB might be a biological target of the synthesized compounds.
European journal of medicinal chemistry 09/2010; 45(9):3938-42. · 3.27 Impact Factor
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Xiao-Dong Wang,
Tian-Miao Ou,
Yu-Jing Lu,
Zeng Li,
Zheng Xu,
Chen Xi,
Jia-Heng Tan,
Shi-Liang Huang,
Lin-Kun An,
Ding Li, Lian-Quan Gu,
Zhi-Shu Huang
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ABSTRACT: Human bcl-2 gene is an apoptosis-related oncogene containing a GC-rich sequence which is located upstream from P1 promoter and has the potential to form G-quadruplex structures. However, the regulatory role of the quadruplex and the effect of its ligands on bcl-2 have not been clarified. Here, we demonstrated that the G-quadruplex structure was disrupted when partial mutation of G --> A was made, resulting in a 2-fold increase in basal transcriptional activity of bcl-2 promoter. Quindoline derivatives, the highly active G-quadruplex ligands developed by our group, could significantly suppress bcl-2 transcriptional activation but had less effect on mutated bcl-2 transcription. These results provided direct evidence that G-quadruplex structure formed in bcl-2 promoter region could function as a transcriptional repressor element, and G-quadruplex specific ligands could regulate the transcription of bcl-2 through stabilization of quadruplex structure. The results further indicated that quindoline derivatives could induce apoptosis of HL-60 tumor cells.
Journal of Medicinal Chemistry 06/2010; 53(11):4390-8. · 4.80 Impact Factor
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Bin Wang,
Yi-Chi Mai,
Yue Li,
Jin-Qiang Hou,
Shi-Liang Huang,
Tian-Miao Ou,
Jia-Heng Tan,
Lin-Kun An,
Ding Li, Lian-Quan Gu,
Zhi-Shu Huang
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ABSTRACT: A series of novel rutaecarpine derivatives and related alkaloid derivatives 3-aminoalkanamido-substituted rutaecarpine 4a-f and 7,8-dehydrorutaecarpine 5a-c, and 6-aminoalkanamido-substituted 3-[2-(3-Indolyl)ethyl]-4(3a)-quinazolinones 8a-c, were synthesized and subjected to pharmacological evaluation as acetylcholinesterase (AChE) inhibitors. The synthetic compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE. The structure-activity relationships were discussed and their binding conformation and simultaneous interactions mode were further clarified by kinetic characterization and the molecular docking studies.
European journal of medicinal chemistry 04/2010; 45(4):1415-23. · 3.27 Impact Factor
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ABSTRACT: In this study we investigated the anti-inflammatory effects of an icariin derivative (3,5-dihydroxy-4'-methoxy-6'',6''-dimethy1-4'',5''-dihydropyrano[2'',3'':7,8]-flavone). We found that this icariin derivative inhibits tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression, and protein expression in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. It also alleviates paw edema induced by carrageenan in mice. To clarify the molecular mechanisms underlying these anti-inflammatory effects, we examined the effects of this compound on the phosphorylation of mitogen-activated protein kinase (MAPK), phosphorylation of inhibitory kappaBalpha (IkappaBalpha), and nuclear translocation of p65 subunit of nuclear factor (NF)-kappaB, and found it suppresses the activation of p38 MAPK and inhibits translocation of NF-kappaB p65 to the nucleus through decreasing the phosphorylation of IkappaBalpha. As a result of these properties, this icariin derivative can be considered as a potential drug for inflammatory diseases.
Biological & Pharmaceutical Bulletin 01/2010; 33(8):1307-13. · 1.66 Impact Factor
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ABSTRACT: Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci gamma-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5-induced gamma-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of gamma-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5.
Molecular Cancer Therapeutics 12/2009; 8(12):3203-13. · 5.23 Impact Factor
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ABSTRACT: A series of oxazolidinone derivatives with alpha-substituted acetylpiperazinyl groups were prepared. Their in vitro antibacterial activities were studied against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. The compounds with chloroacetyl-piperazinyl or dichloroacetyl-piperazinyl group were found to have superior antibacterial activities to linezolid against most of tested Gram-positive pathogens. The compounds with propionylpiperaziny or fluoroacetylpiperazinyl group were found to have comparable antibacterial activities with linezolid. However, the replacement of phenyl ring of the compounds with pyridine ring resulted in the significant loss of antibacterial activity.
Chemical Biology & Drug Design 10/2009; 74(3):276-81. · 2.28 Impact Factor
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ABSTRACT: A series of oxazolidinone derivatives with -substituted acetylpiperazinyl groups were prepared. Their in vitro antibacterial activities were studied against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. The compounds with chloroacetyl-piperazinyl or dichloroacetyl-piperazinyl group were found to have superior antibacterial activities to linezolid against most of tested Gram-positive pathogens. The compounds with propionylpiperaziny or fluoroacetylpiperazinyl group were found to have comparable antibacterial activities with linezolid. However, the replacement of phenyl ring of the compounds with pyridine ring resulted in the significant loss of antibacterial activity.
Chemical Biology & Drug Design 08/2009; 74(3):276 - 281. · 2.28 Impact Factor
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ABSTRACT: A series of new 9-O-substituted berberine derivatives (4a-j) as telomeric quadruplex ligands was synthesized and evaluated. The results from biophysical and biochemical assay indicated that introducing of positive charged aza-aromatic terminal group into the side chain of 9-position of berberine significantly improved the binding ability with G-quadruplex, and exhibited the inhibitory effect on the hybridization and on telomerase activity. These derivatives showed excellent selectivity for telomeric G-quadruplex DNA over duplex.
Bioorganic & medicinal chemistry letters 08/2009; 19(13):3414-7. · 2.65 Impact Factor
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ABSTRACT: A series of eperezolid analogs with glycinyl substitutions were prepared and their antibacterial activities were studied against a panel of susceptible and resistant Gram-positive bacteria. The compounds with N-arylacyl or N-heteroarylacyl glycinyl structural units showed good antibacterial activities. The compounds 11b, 11c, and 11e were twofold more active than linezolid against Staphylococcus epidermidis and Enterococcus faecalis. Several pyridine analogs were also prepared and found to have poor antibacterial activity against most of the tested Gram-positive bacteria, however, one of the compounds 12e showed very high activity against Enterococcus faecalis.
Archiv der Pharmazie 07/2009; 342(7):377-85. · 1.71 Impact Factor
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ABSTRACT: A series of icariin derivatives were synthesized. Their multidrug resistance (MDR) reversal activities were evaluated by MTT assay and the results indicated that the derivatives were the potent modulators of MDR. It was showed that the derivatives significantly increased the intracellular accumulation of ADR in MCF-7/ADR cells compared with drug sensitive MCF-7 cells. The results of bi-directional assay and reverse transcription polymerase chain reaction (RT-PCR) assay showed that the derivatives had high inhibitory activity against P-gp efflux function and significantly down-regulated on the expression of P-gp.
Bioorganic & medicinal chemistry letters 06/2009; 19(15):4237-40. · 2.65 Impact Factor
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ABSTRACT: Four isaindigotone derivatives (5a,b and 6a,b) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The unfused aromatic rings in these compounds allow a flexible and adaptive conformation in G-quadruplex recognition. The interaction of human telomeric G-quadruplex DNA with these designed ligands was explored by means of FRET melting, fluorescence titration, CD spectroscopy, continuous variation, and molecular modeling studies. Our results showed that the adaptive scaffold might not only allow the ligands to well occupy the G-quartet but also perfectly bind to the grooves of the G-quadruplex. The synergetic effect of the multiple binding modes might be responsible for the improved binding ability and high selectivity of these ligands toward G-quadruplex over duplex DNA. Long-term exposure of HL60 and CA46 cancer cells to compound 5a showed a remarkable decrease in population growth, cellular senescence phenotype, and shortening of the telomere length, which is consistent with the behavior of an effective telomeric G-quadruplex ligand and telomerase inhibitor.
Journal of Medicinal Chemistry 05/2009; 52(9):2825-35. · 4.80 Impact Factor
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ABSTRACT: A series of new natural tanshinone-like oxoheterocyclic-fused ortho-quinone derivatives were synthesized from readily available benzofuranol and N-substituted dienes via IBX oxidation-cycloaddition-aromatization procedure. The regiospecific Diels-Alder cycloaddition reactions of N-dienes were achieved efficiently with a variety of dienophiles. It is found that the amide moiety in the molecular could be preserved or eliminated by control of the aromatization conditions. Selected oxoheterocyclic-fused ortho-quinones as well as several thioheterocyclic-fused ortho-quinones we obtained before were evaluated for their cytotoxicities on different cancer cell lines and the Structure-Activity Relationship (SAR) was discussed.
European journal of medicinal chemistry 05/2009; 44(10):3915-21. · 3.27 Impact Factor
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ABSTRACT: Six 3-methylpyridine zwitterions and six quinoline zwitterions were synthesized through the reaction of 4-hydroxycoumarins, p-benzoquinone and the corresponding N-aromatics. The novel pseudo-cyclic face-to-face rigid structure of the zwitterion was elucidated by (1)H-NMR at different temperatures, and assumed to be caused by both the intramolecular ion pair attraction and the steric interaction.
Molecules 02/2009; 14(4):1546-60. · 2.39 Impact Factor
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ABSTRACT: Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.
European journal of medicinal chemistry 02/2009; 44(6):2523-32. · 3.27 Impact Factor
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ABSTRACT: G-quadruplex structures are promising targets for design of cancer drugs with high selectivity and low toxicity. This review provides an update of the progress made over the last few years in the design of selective G-quadruplex ligands, and a comprehensive summary of the major design strategies and structural characteristics.
Mini Reviews in Medicinal Chemistry 11/2008; 8(11):1163-78. · 2.53 Impact Factor
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ABSTRACT: Carbohydrate microarrays have attracted increasing attention in recent years because of their ability to monitor biologically important protein-carbohydrate interactions in a high-throughput manner. Here we have developed an effective approach to immobilizing intact carbohydrates directly on polystyrene microtiter plates coated with amine-functionalized sol-gel monolayers. Lectin binding was monitored by fluorescence spectroscopy using these covalent arrays of carbohydrates that contained six mono- and di-saccharides on the microplates. In addition, binding affinities of lectin to carbohydrates were also quantitatively analyzed by determining IC(50) values of lectin-specific antibody with these arrays. Our results indicate that microplate-based carbohydrate arrays can be efficiently fabricated by covalent immobilization of intact carbohydrates on sol-gel-coated microplates. The microplate-based carbohydrate arrays can be applied for screening of protein-carbohydrate interactions in a high-throughput manner.
The Analyst 10/2008; 133(9):1195-200. · 4.23 Impact Factor
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ABSTRACT: Mammalian thioredoxin reductase (TrxR), a ubiquitous selenocysteine containing oxidoreductase, catalyzes the NADPH-dependent reduction of oxidized thioredoxin (Trx). TrxR has been suggested as a potential target for anticancer drugs development for its overexpression in human tumors and its diverse functions in intracellular redox control, cell growth and apoptosis. Mansonone F (MF) compounds have been shown to exhibit antiproliferative effects, but their complex mechanisms are unknown. In the present study, we have investigated the effects of some synthesized MF analogues on TrxR and HeLa cells. The studies of the mode of inhibition and the interactions of IG3, one of the most potent MF analogues, with TrxR showed MF compounds could be partly reduced by the C-terminal selenolthiol active site, and possibly by the N-terminal dithiol motif and/or FAD domain of TrxR simultaneously, accompanied by redox cycling with the generation of superoxide anion radicals. In addition, MF analogues exhibited the potential to inhibit the growth of HeLa cells and reduce TrxR activity in cell lysates. The cell cycle was arrested in G2/M phase and apoptosis was induced in a dose-dependent manner. Furthermore, our results showed that IG3-treated HeLa cells induced the change of intracellular ROS. Taken together, the reported results here suggest that inhibition of TrxR by MF analogues provides a possible complex mechanism for explaining the anticancer activity of MF compounds.
Chemico-biological interactions 10/2008; 177(1):48-57. · 2.46 Impact Factor
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Yu-Jing Lu,
Tian-Miao Ou,
Jia-Heng Tan,
Jin-Qiang Hou,
Wei-Yan Shao,
Dan Peng,
Ning Sun,
Xiao-Dong Wang,
Wei-Bin Wu,
Xian-Zhang Bu,
Zhi-Shu Huang,
Dik-Lung Ma,
Kwok-Yin Wong, Lian-Quan Gu
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ABSTRACT: A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.
Journal of Medicinal Chemistry 10/2008; 51(20):6381-92. · 4.80 Impact Factor
