45 results on '"Tian-Miao Ou"'
Search Results
2. Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
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Shi-Liang Huang, Qi-Kun Yin, Jia-En Wang, Honggen Wang, Ding Li, Chen-Xi Wang, Jia-Heng Tan, Zhi-Shu Huang, Yao-Hao Xu, Yong Rao, Zi-Lin Zhang, Shuo-Bin Chen, Tian-Miao Ou, Jia-Li Tu, and Qingjiang Li
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Models, Molecular ,congenital, hereditary, and neonatal diseases and abnormalities ,Protein Conformation ,DNA damage ,Poly ADP ribose polymerase ,Apoptosis ,Chemistry Techniques, Synthetic ,Poly(ADP-ribose) Polymerase Inhibitors ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Polymerase ,Cell Proliferation ,Quinazolinones ,030304 developmental biology ,0303 health sciences ,RecQ Helicases ,biology ,urogenital system ,Chemistry ,nutritional and metabolic diseases ,Helicase ,Drug Synergism ,Telomere ,HCT116 Cells ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,Bloom syndrome protein ,Drug Design ,Cancer cell ,biology.protein ,Molecular Medicine ,DNA ,DNA Damage - Abstract
DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.
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- 2020
3. Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[ c ]acridine derivatives as new c- KIT promoter G-quadruplex binding ligands
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Qian-Liang Guo, Ding Li, Jia-Heng Tan, Yu-Ting Lu, Zhi-Shu Huang, Hua-Fei Su, Ning Wang, Tian-Miao Ou, and Sheng-Rong Liao
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0301 basic medicine ,Molecular model ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,Ligands ,010402 general chemistry ,G-quadruplex ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Transcription (biology) ,Drug Discovery ,Humans ,heterocyclic compounds ,Promoter Regions, Genetic ,Cell Proliferation ,Pharmacology ,Cell growth ,Organic Chemistry ,General Medicine ,Ligand (biochemistry) ,0104 chemical sciences ,G-Quadruplexes ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,chemistry ,Biochemistry ,Acridine ,Acridines ,K562 Cells ,DNA - Abstract
It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize c-KIT G-quadruplex with good selectivity against duplex DNA. It was found that 12-N-methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[c]acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway.
- Published
- 2017
4. Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole
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Tian-Miao Ou, Ming-Hao Hu, Bo Wang, Jia-Heng Tan, Lian-Quan Gu, Zhi-Shu Huang, and Shuo-Bin Chen
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Models, Molecular ,0301 basic medicine ,Senescence ,Cell cycle checkpoint ,Transcription, Genetic ,Cell Survival ,Oligonucleotides ,Biology ,G-quadruplex ,03 medical and health sciences ,Chemical Biology and Nucleic Acid Chemistry ,Transcription (biology) ,Cell Line, Tumor ,Genetics ,Humans ,heterocyclic compounds ,Cell Proliferation ,Molecular Structure ,Spectrum Analysis ,Imidazoles ,DNA ,Oncogenes ,Telomere ,Cell biology ,G-Quadruplexes ,030104 developmental biology ,Cell culture ,Apoptosis ,Cancer cell ,Nucleic Acid Conformation ,DNA Damage - Abstract
Multiple G-quadruplex units in the 3΄-terminal overhang of human telomeric DNA can associate and form multimeric structures. The specific targeting of such distinctive higher-order G-quadruplexes might be a promising strategy for developing selective anticancer agents with fewer side effects. However, thus far, only a few molecules were found to selectively bind to telomeric multimeric G-quadruplexes, and their effects on cancer cells were unknown. In this study, a new triaryl-substituted imidazole derivative called IZNP-1 was synthesized and found to specifically bind to and strongly stabilize telomeric multimeric G-quadruplexes through intercalating into the pocket between the two quadruplex units. The pocket size might affect the binding behavior of IZNP-1. Further cellular studies indicated that IZNP-1 could provoke cell cycle arrest, apoptosis and senescence in Siha cancer cells, mainly because of telomeric DNA damage and telomere dysfunction induced by the interactions of IZNP-1 with telomeric G-quadruplexes. Notably, IZNP-1 had no effect on the transcriptional levels of several common oncogenes that have the potential to form monomeric G-quadruplex structures in their promoter regions. Such behavior differed from that of traditional telomeric G-quadruplex ligands. Accordingly, this work provides new insights for the development of selective anticancer drugs targeting telomeric multimeric G-quadruplexes.
- Published
- 2016
5. Discovery of Isaindigotone Derivatives as Novel Bloom's Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair
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Zhi-Shu Huang, Tian-Miao Ou, Shi-Liang Huang, Zi-Lin Zhang, Yu-Qing Wang, Honggen Wang, Jia-Heng Tan, Shuo-Bin Chen, Ding Li, Qi-Kun Yin, Qian-Liang Guo, and Chen-Xi Wang
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congenital, hereditary, and neonatal diseases and abnormalities ,DNA damage ,RAD51 ,Apoptosis ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Alkaloids ,Drug Discovery ,Humans ,DNA Breaks, Double-Stranded ,Enzyme Inhibitors ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,biology ,RecQ Helicases ,urogenital system ,Drug discovery ,nutritional and metabolic diseases ,Helicase ,Recombinational DNA Repair ,DNA ,HCT116 Cells ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,chemistry ,Bloom syndrome protein ,Cancer cell ,biology.protein ,Quinazolines ,Molecular Medicine ,Rad51 Recombinase ,Homologous recombination - Abstract
Homologous recombination repair (HRR), a crucial approach in DNA damage repair, is an attractive target in cancer therapy and drug design. The Bloom syndrome protein (BLM) is a 3′–5′ DNA helicase that performs an important role in HRR regulation. However, limited studies about BLM inhibitors and their biological effects have been reported. Here, we identified a class of isaindigotone derivatives as novel BLM inhibitors by synthesis, screening, and evaluating. Among them, compound 29 was found as an effective BLM inhibitor with a high binding affinity and good inhibitory effect on BLM. Cellular evaluation indicated that 29 effectively disrupted the recruitment of BLM at DNA double-strand break sites, promoted an accumulation of RAD51, and regulated the HRR process. Meanwhile, 29 significantly induced DNA damage responses, as well as apoptosis and proliferation arrest in cancer cells. Our finding provides a potential anticancer strategy based on interfering with BLM via small molecules.
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- 2019
6. Design, Synthesis, and Evaluation of Novel p-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex
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Zhi-Yin Sun, Shi-Ke Wang, Guo-Tao Kuang, Zhi-Shu Huang, Xiao-Na Wang, Jia-Heng Tan, Wang Peng, Xiao-Xuan Su, Tian-Miao Ou, Qi Zhang, and Sui-Qi Cheng
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Indoles ,Stereochemistry ,Repressor ,Chemistry Techniques, Synthetic ,G-quadruplex ,Proto-Oncogene Mas ,GTP Phosphohydrolases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alkaloids ,Cell Line, Tumor ,Drug Discovery ,Humans ,heterocyclic compounds ,Styrene ,Messenger RNA ,RNA ,Membrane Proteins ,Translation (biology) ,Cell Cycle Checkpoints ,G-Quadruplexes ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Drug Design ,Quinolines ,Molecular Medicine ,DNA - Abstract
The human proto-oncogene neuroblastoma RAS ( NRAS) contains a guanine-rich sequence in the 5'-untranslated regions (5'-UTR) of the mRNA that could form an RNA G-quadruplex structure. This structure acts as a repressor for NRAS translation and could be a potential target for anticancer drugs. Our previous studies found an effective scaffold, the quindoline scaffold, for binding and stabilizing the DNA G-quadruplex structures. Here, on the basis of the previous studies and reported RNA-specific probes, a series of novel p-(methylthio)styryl substituted quindoline (MSQ) derivatives were designed, synthesized, and evaluated as NRAS RNA G-quadruplex ligands. Panels of experiments turned out that the introduction of p-(methylthio)styryl side chain could enhance the specific binding to the NRAS RNA G-quadruplex. One of the hits, 4a-10, showed strong stabilizing activity on the G-quadruplex and subsequently repressed NRAS's translation and inhibited tumor cells proliferation. Our finding provided a novel strategy to discover novel NRAS repressors by specifically binding to the RNA G-quadruplex in the 5'-UTR of mRNA.
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- 2018
7. Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response
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Zeng-Qing Wang, Bo Wang, Jia-Heng Tan, Yong Zhao, Yu-Qing Wang, Tian-Miao Ou, Ze-Peng Zhang, Yan Zhang, Jia-Li Tu, Shuo-Bin Chen, Jing Wang, Tong Che, and Zhi-Shu Huang
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0301 basic medicine ,Cell cycle checkpoint ,Indoles ,DNA damage ,Telomere-Binding Proteins ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,Apoptosis ,010402 general chemistry ,G-quadruplex ,Ligands ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,heterocyclic compounds ,Cytotoxicity ,Telomerase ,Telomere Shortening ,Cell Proliferation ,Mice, Inbred BALB C ,Chemistry ,DNA ,Telomere ,Xenograft Model Antitumor Assays ,0104 chemical sciences ,Cell biology ,G-Quadruplexes ,G2 Phase Cell Cycle Checkpoints ,030104 developmental biology ,Cell culture ,Molecular Medicine ,Female ,DNA Damage - Abstract
Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands.
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- 2018
8. Role of Hairpin-Quadruplex DNA Secondary Structural Conversion in the Promoter of hnRNP K in Gene Transcriptional Regulation
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Ding Li, Jun Qiu, Zhi-Shu Huang, Jia-Heng Tan, Tian-Miao Ou, Jinggong Liu, Lian-Quan Gu, and Shuo-Bin Chen
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Guanine ,RNA-binding protein ,G-quadruplex ,environment and public health ,Biochemistry ,Heterogeneous-Nuclear Ribonucleoprotein K ,Cytosine ,chemistry.chemical_compound ,Transcription (biology) ,Transcriptional regulation ,heterocyclic compounds ,Regulatory Elements, Transcriptional ,Physical and Theoretical Chemistry ,Promoter Regions, Genetic ,Gene ,Base Sequence ,Molecular Structure ,Organic Chemistry ,RNA-Binding Proteins ,DNA ,Molecular biology ,G-Quadruplexes ,chemistry ,Nucleic Acid Conformation - Abstract
The promoter of hnRNP K oncogene was found to contain a G/C-rich sequence on the same DNA strand, which can form interconvertible G-quadruplex, i-motif, and hairpin structures. Protein CNBP could bind and stabilize the G-quadruplex, inducing transformation of the hairpin into the G-quadruplex, resulting in down-regulation of hnRNP K transcription. In contrast, Corticosterone could bind and stabilize the hairpin, inducing transformation of the G-quadruplex into the hairpin, resulting in up-regulation of hnRNP K gene transcription.
- Published
- 2015
9. Chemical intervention of the NM23-H2 transcriptional programme onc-MYCvia a novel small molecule
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Hui-Yun Liu, Jia-Heng Tan, Zhi-Shu Huang, Ding Li, Chan Shan, Ai-Chun Chen, Shuo-Bin Chen, Lian-Quan Gu, Jin-Qiang Hou, Jing Lin, and Tian-Miao Ou
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Transcription, Genetic ,Response element ,Down-Regulation ,Apoptosis ,Biology ,Proto-Oncogene Proteins c-myc ,Small Molecule Libraries ,Mice ,Upstream activating sequence ,Epigenetics of physical exercise ,Chemical Biology and Nucleic Acid Chemistry ,Transcription (biology) ,Genetics ,Transcriptional regulation ,Animals ,Humans ,Promoter Regions, Genetic ,Transcription factor ,Cells, Cultured ,Quinazolinones ,General transcription factor ,Promoter ,DNA ,NM23 Nucleoside Diphosphate Kinases ,Molecular biology ,Cell biology ,HeLa Cells ,Protein Binding - Abstract
c-MYC is an important oncogene that is considered as an effective target for anticancer therapy. Regulation of this gene's transcription is one avenue for c-MYC-targeting drug design. Direct binding to a transcription factor and generating the intervention of a transcriptional programme appears to be an effective way to modulate gene transcription. NM23-H2 is a transcription factor for c-MYC and is proven to be related to the secondary structures in the promoter. Here, we first screened our small-molecule library for NM23-H2 binders and then sifted through the inhibitors that could target and interfere with the interaction process between NM23-H2 and the guanine-rich promoter sequence of c-MYC. As a result, a quinazolone derivative, SYSU-ID-01: , showed a significant interference effect towards NM23-H2 binding to the guanine-rich promoter DNA sequence. Further analyses of the compound-protein interaction and the protein-DNA interaction provided insight into the mode of action for SYSU-ID-01: . Cellular evaluation results showed that SYSU-ID-01: could abrogate NM23-H2 binding to the c-MYC promoter, resulting in downregulation of c-MYC transcription and dramatically suppressed HeLa cell growth. These findings provide a new way of c-MYC transcriptional control through interfering with NM23-H2 binding to guanine-rich promoter sequences by small molecules.
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- 2015
10. Biological Function and Medicinal Research Significance of G-Quadruplex Interactive Proteins
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Mingxue Wang, Jia-Heng Tan, Tian-Miao Ou, Lian-Quan Gu, Jun Qiu, Yan Zhang, Honggen Wang, Shi-Liang Huang, Zhi-Shu Huang, Ping Zeng, Lin-Kun An, and Ding Li
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Drug discovery ,DNA replication ,General Medicine ,Biology ,G-quadruplex ,DNA-binding protein ,Cell biology ,DNA-Binding Proteins ,G-Quadruplexes ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Transcription (biology) ,Drug Discovery ,Antigenic variation ,Animals ,Humans ,heterocyclic compounds ,Molecular Targeted Therapy ,Epigenetics ,DNA - Abstract
G-quadruplexes are four-stranded DNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Accumulating studies have revealed that G-quadruplex structures are formed in vivo and play important roles in biological processes such as DNA replication, transcription, recombination, epigenetic regulation, meiosis, antigenic variation, and maintenance of telomeres stability. Mounting evidence indicates that a variety of proteins are capable of binding selectively and tightly to G-quadruplex and play essential roles in G-quadruplex-mediated regulation processes. Some of these proteins promote the formation or/and stabilization of G-quadruplex, while some other proteins act to unwind G-quadruplex preferentially. From a drug discovery perspective, many of these G-quadruplex binding proteins and/or their complexes with G-quadruplexes are potential drug targets. Here, we present a general summary of reported G-quadruplex binding proteins and their biological functions, with focus on those of medicinal research significance. We elaborated the possibility for some of these G-quadruplex binding proteins and their complexes with G-quadruplexes as potential drug targets.
- Published
- 2015
11. Synthesis and evaluation of new BODIPY-benzofuroquinoline conjugates for sensitive and selective DNA detection
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Lian-Quan Gu, Ding Li, Hua Wenzhao, Zhi-Shu Huang, Tian-Miao Ou, Shuo-Bin Chen, Shi-Liang Huang, Su-Mei Huang, Gang Du, Peng Zhai, and Jia-Heng Tan
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Process Chemistry and Technology ,General Chemical Engineering ,Isothermal titration calorimetry ,Fluorescence ,Combinatorial chemistry ,Fluorescence spectroscopy ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Nucleic acid ,A-DNA ,Titration ,BODIPY ,DNA - Abstract
The sensitive and selective detection of nucleic acids is important for basic research and many applied fields. Herein, a series of new BODIPY-benzofuroquinoline conjugates were designed, synthesized and evaluated as DNA intercalating dyes. All compounds were characterized by using 1H, 13C NMR, IR, UV–Vis and fluorescence spectroscopy, and DNA binding properties of these conjugates to calf thymus DNA were studied by using fluorescence titration, UV titration, isothermal titration calorimetry and CD analysis. Significant enhancement of the fluorescent quantum yield was observed for all the conjugates in the presence of calf thymus DNA, and one compound showed excellent sensitivity and selectivity offering its potential application as a DNA specific fluorescent probe. Our results showed that these conjugates could intercalate into calf thymus DNA with high binding affinities. The properties of these dyes as fluorescent probes for living cells imaging were also investigated.
- Published
- 2014
12. Facile syntheses of disubstituted bis(vinylquinolinium)benzene derivatives as G-quadruplex DNA binders
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Tian-Miao Ou, Shi-Tian Zhuo, Zhen-Quan Liu, Lian-Quan Gu, Jia-Heng Tan, Ding Li, and Zhi-Shu Huang
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Circular dichroism ,Molecular model ,Organic Chemistry ,G-quadruplex ,Biochemistry ,Medicinal chemistry ,chemistry.chemical_compound ,Förster resonance energy transfer ,chemistry ,Yield (chemistry) ,Drug Discovery ,Side chain ,Organic chemistry ,Amine gas treating ,DNA - Abstract
A series of disubstituted bis(vinylquinolinium)benzene derivatives were designed, which were prepared through a facile three-component one-pot reaction in good yield. FRET results showed that 1,3-disubstituted benzene derivatives had much stronger stabilization effect on G-quadruplex DNA than that of 1,4-disubstituted benzene derivatives. The introduction of substituted amine side chain at quinolinium obviously increased the binding affinity of compounds to G-quadruplex DNA. It was also found that 1,3-disubstituted benzene derivatives and 1,4-disubstituted benzene derivatives had different effects on the conformation of G-quadruplex DNA by CD spectroscopy analysis. The differences for the interactions of these two classes of compounds with G-quadruplex were further studied and elaborated through molecular modeling experiments.
- Published
- 2013
13. New quinazoline derivatives for telomeric G-quadruplex DNA: Effects of an added phenyl group on quadruplex binding ability
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Lian-Quan Gu, Lin-Kun An, Jia-Heng Tan, Zhi-Shu Huang, Jin-Hui He, Hui-Yun Liu, Shi-Liang Huang, Ding Li, Tian-Miao Ou, and Zeng Li
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Cell Survival ,Stereochemistry ,HL-60 Cells ,Ligands ,G-quadruplex ,Binding, Competitive ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Phenyl group ,Molecule ,Benzamide ,Telomerase ,Cellular Senescence ,Telomere Shortening ,Pharmacology ,Molecular Structure ,Phenol ,Hydrogen bond ,Circular Dichroism ,Organic Chemistry ,DNA ,General Medicine ,Surface Plasmon Resonance ,Telomere ,G-Quadruplexes ,Kinetics ,chemistry ,Intramolecular force ,Quinazolines ,Selectivity - Abstract
To improve the selectivity of indoloquinoline or benzofuroquinoline derivatives, we previously reported several quinazoline derivatives [17]. These compounds could mimic a tetracyclic aromatic system through intramolecular hydrogen bond. Studies showed that these quinazoline derivatives were effective and selective telomeric G-quadruplex ligands. With this encouragement, here we synthesized a series of N-(2-(quinazolin-2-yl)phenyl)benzamide (QPB) compounds as modified quinazoline derivatives. In this modification, a phenyl group was introduced to the aromatic core. The evaluation results showed that part of QPB derivatives had stronger binding ability and better selectivity for telomeric G-quadruplex DNA than LZ-11, the most potential compound of reported quinazoline derivatives. Furthermore, telomerase inhibition of QPB derivatives and their cellular effects were studied.
- Published
- 2013
14. Design, synthesis and biological evaluation of 4-anilinoquinazoline derivatives as new c-myc G-quadruplex ligands
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Jia-Heng Tan, Tian-Miao Ou, Ai-Chun Chen, Shi-Ke Wang, Jiang Yin, Zhi-Shu Huang, Ding Li, and Guo-Tao Kuang
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0301 basic medicine ,Transcription, Genetic ,Down-Regulation ,Chemistry Techniques, Synthetic ,G-quadruplex ,Ligands ,HeLa ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Western blot ,Transcription (biology) ,Drug Discovery ,medicine ,Quinazoline ,Animals ,Humans ,Cell Proliferation ,Pharmacology ,medicine.diagnostic_test ,biology ,Chemistry ,Cell growth ,Organic Chemistry ,General Medicine ,Ligand (biochemistry) ,biology.organism_classification ,Molecular biology ,G-Quadruplexes ,030104 developmental biology ,Biochemistry ,Drug Design ,Quinazolines ,DNA - Abstract
A series of 4-anilinoquinazoline derivatives were designed and synthesized as novel c-myc promoter G-quadruplex binding ligands. Subsequent biophysical and biochemical evaluation demonstrated that the introduction of aniline group at 4-position of quinazoline ring and two side chains with terminal amino group improved their binding affinity and stabilizing ability to G-quadruplex DNA. RT-PCR assay and Western blot showed that compound 7a could down-regulate transcription and expression of c-myc gene in Hela cells, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene. More importantly, RTCA and colony formation assays indicated that 7a obviously inhibited Hela cells proliferation, without influence on normal primary cultured mouse mesangial cells. Flow cytometric assays suggested that 7a induced Hela cells to arrest in G0/G1 phase both in a time-dependent and dose-dependent manner.
- Published
- 2016
15. Accurate high-throughput identification of parallel G-quadruplex topology by a new tetraaryl-substituted imidazole
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Ding Li, You-Mei Zeng, Yu-Qing Wang, Zhi-Shu Huang, Jia-Heng Tan, Tian-Miao Ou, Shuo-Bin Chen, Lian-Quan Gu, and Ming-Hao Hu
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0301 basic medicine ,Biomedical Engineering ,Biophysics ,Nanotechnology ,Biosensing Techniques ,Biology ,G-quadruplex ,03 medical and health sciences ,chemistry.chemical_compound ,Electrochemistry ,Imidazole ,heterocyclic compounds ,Fluorescent Dyes ,Oligonucleotide ,Imidazoles ,RNA ,General Medicine ,DNA ,Fluorescence spectra ,High-Throughput Screening Assays ,G-Quadruplexes ,030104 developmental biology ,Spectrometry, Fluorescence ,chemistry ,Nucleic acid ,Colorimetry ,Biological system ,Biotechnology - Abstract
G-quadruplex nucleic acids are four-stranded DNA or RNA secondary structures that are formed in guanine-rich sequences. These structures exhibit extensive structural polymorphism and play a pivotal role in the control of a variety of cellular processes. To date, diverse approaches for high-throughput identification of G-quadruplex structures have been successfully developed, but high-throughput methods for further characterization of their topologies are still lacking. In this study, we report a new tetra-arylimidazole probe psIZCM-1, which was found to display significant and distinctive changes in both the absorption and the fluorescence spectra in the presence of parallel G-quadruplexes but show insignificant changes upon interactions with anti-parallel G-quadruplexes or other non-quadruplex oligonucleotides. In view of this dual-output feature, we used psIZCM-1 to identify the parallel G-quadruplexes from a large set of 314 oligonucleotides (including 300 G-quadruplex-forming oligonucleotides and 14 non-quadruplex oligonucleotides) via a microplate reader and accordingly established a high-throughput method for the characterization of parallel G-quadruplex topologies. The accuracy of this method was greater than 95%, which was much higher than that of the commercial probe NMM. To make the approach more practical, we further combined psIZCM-1 with another G-quadruplex probe IZCM-7 to realize the high-throughput classification of parallel, anti-parallel G-quadruplexes and non-quadruplex structures.
- Published
- 2016
16. 12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA
- Author
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Lian-Quan Gu, Zhi-Shu Huang, Sheng-Rong Liao, Jia-Heng Tan, Tian-Miao Ou, Wei-Bin Wu, Chen-Xi Zhou, and Ding Li
- Subjects
Models, Molecular ,Circular dichroism ,Transcription, Genetic ,Molecular model ,Stereochemistry ,Antineoplastic Agents ,Ligands ,Nucleic Acid Denaturation ,G-quadruplex ,Methylation ,Substrate Specificity ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Transcription (biology) ,Cell Line, Tumor ,Drug Discovery ,Humans ,Transition Temperature ,Surface plasmon resonance ,Cell Proliferation ,Pharmacology ,Base Sequence ,Organic Chemistry ,DNA ,General Medicine ,Reverse transcriptase ,G-Quadruplexes ,Förster resonance energy transfer ,chemistry ,Drug Design ,Acridines - Abstract
12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), polymerase chain reaction (PCR) stop assay, and molecular modeling. Compared with the non-methylated derivatives, 12-N-methylated derivatives had stronger binding affinity and stabilizing ability to c-myc G-quadruplex structure, and could more effectively stack on the G-quartet surface. All these derivatives had high selectivity for c-myc G-quadruplex DNA over duplex DNA. The reverse transcription (RT) PCR assay showed that compound 21c could down-regulate transcription of c-myc gene in Ramos cell line containing NHE III(1) element, but had no effect in CA46 cell line with NHE III(1) element removed.
- Published
- 2012
17. Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3-b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors
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Jia-Heng Tan, Yan-Wen Mai, Shi-Liang Huang, Pei-Fen Yao, Peng-Hui Li, Shuo-Bin Chen, Zhi-Shu Huang, Ping Zeng, Ding Li, Tian-Miao Ou, and Lian-Quan Gu
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0301 basic medicine ,Models, Molecular ,Pyrazine ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Humans ,Topoisomerase II Inhibitors ,Pyrroles ,Binding site ,Cell Proliferation ,biology ,010405 organic chemistry ,Cell growth ,Receptors, Purinergic P2 ,Topoisomerase ,DNA Helicases ,DNA ,0104 chemical sciences ,Molecular Docking Simulation ,030104 developmental biology ,DNA Topoisomerases, Type II ,chemistry ,Cell culture ,Pyrazines ,biology.protein ,Molecular Medicine ,Topoisomerase-II Inhibitor ,Drug Screening Assays, Antitumor - Abstract
Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of 1,3-benzoazolyl-substituted pyrrolo[2,3-b]pyrazine derivatives were designed, synthesized, and evaluated as potential Topo II catalytic inhibitors. It was found that some of derivatives had good antiproliferative activity on seven cancer cell lines, especially on HL-60/MX2, a cancer cell line derivative from HL-60 that is resistant to Topo II poison. Topo II mediated DNA relaxation assay results showed that derivatives could significantly inhibit the activity of Topo II, and the structure-activity relationship studies indicated the importance of the alkylamino side chain and the benzoazolyl group. Further mechanism studies revealed that derivatives function as Topo II nonintercalative catalytic inhibitors and may block the ATP binding site of Topo II. Moreover, flow cytometric analysis showed that this class of compounds could induce apoptosis of HL-60 cells.
- Published
- 2015
18. Synthesis and evaluation of mansonone F derivatives as topoisomerase inhibitors
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Shuo-Bin Chen, Jie-Bin Ou, Jia-Heng Tan, Ding Li, Zhi-Shu Huang, Tian-Miao Ou, Liu-Lan Shen, Lian-Quan Gu, Shi-Liang Huang, Zhi-Hong Huang, and Wei-Bin Wu
- Subjects
Lung Neoplasms ,Cell Survival ,Topoisomerase Inhibitors ,medicine.drug_class ,Stereochemistry ,Adenocarcinoma of Lung ,Antineoplastic Agents ,Adenocarcinoma ,Topoisomerase-I Inhibitor ,Chemical synthesis ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Antigens, Neoplasm ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Cytotoxicity ,Telomerase ,Etoposide ,Pyrans ,Pharmacology ,Nasopharyngeal Carcinoma ,biology ,Topoisomerase ,Carcinoma ,Organic Chemistry ,Quinones ,Nasopharyngeal Neoplasms ,DNA ,General Medicine ,DNA-Binding Proteins ,DNA Topoisomerases, Type II ,DNA Topoisomerases, Type I ,chemistry ,Biochemistry ,Enzyme inhibitor ,Pyran ,biology.protein ,Drug Screening Assays, Antitumor ,Sesquiterpenes ,Topoisomerase inhibitor ,Naphthoquinones ,Plasmids ,medicine.drug - Abstract
A series of mansonone F (MF) derivatives were designed and synthesized. These compounds were found to be strong inhibitors for topoisomerases, with much more significant inhibition for topoisomerase II rather than topoisomerase I. The best inhibitor showed 20 times stronger anti-topoisomerase II activity than a positive control Etoposide. The cytotoxic activity of these MF derivatives was evaluated against human cancer cell lines CNE-2 and Glc-82, which showed that these compounds were potent antitumor agents. The structure–activity relationships (SARs) study revealed that o-quinone group and pyran ring are important for their cytotoxic activity.
- Published
- 2011
19. Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds derived from berberine: A new class of highly selective ligands for G-quadruplex DNA in c-myc oncogene
- Author
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Lian-Quan Gu, Zhi-Shu Huang, Jia-Heng Tan, Tian-Miao Ou, Jin-Qiang Hou, Shi-Liang Huang, and Yan Ma
- Subjects
Models, Molecular ,Berberine ,Transcription, Genetic ,Stereochemistry ,Guanine ,HL60 ,Down-Regulation ,Antineoplastic Agents ,HL-60 Cells ,Ligands ,G-quadruplex ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Drug Discovery ,Humans ,heterocyclic compounds ,Cells, Cultured ,Cell Proliferation ,Pharmacology ,Molecular Structure ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Ligand ,Alkaloid ,Organic Chemistry ,Stereoisomerism ,DNA ,General Medicine ,Isoquinolines ,G-Quadruplexes ,chemistry ,Biochemistry ,Quinolines ,Thermodynamics ,Drug Screening Assays, Antitumor - Abstract
A series of quinolino-benzo-[5, 6]-dihydroisoquindolium compounds (3a, 3f, 3g, and 3j) derived from alkaloid berberine were designed and synthesized as novel G-quadruplex ligands. Subsequent biophysical and biochemical evaluation demonstrated that the addition of pyridine ring and amino group into berberine improved the binding ability and selectivity towards G-quadruplex DNA in comparison with the previously reported 9-N-substituted berberine derivatives. Furthermore, qRT-PCR assay showed compound 3j led the down-regulation of c-myc gene transcription in leukemia cell line HL60, while little effect on normal cell line ECV-304, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene.
- Published
- 2011
20. New Insights into the Structures of Ligand−Quadruplex Complexes from Molecular Dynamics Simulations
- Author
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Lian-Quan Gu, Jin-Qiang Hou, Tian-Miao Ou, Jia-Heng Tan, Jun Xu, Zhi-Shu Huang, Hai-Bin Luo, Shuo-Bin Chen, and Ding Li
- Subjects
Models, Molecular ,Aqueous solution ,Molecular Structure ,Stereochemistry ,Hydrogen bond ,Chemistry ,RNA ,Hydrogen Bonding ,DNA ,Molecular Dynamics Simulation ,Telomere ,Ligands ,Ligand (biochemistry) ,Surfaces, Coatings and Films ,G-Quadruplexes ,Molecular dynamics ,chemistry.chemical_compound ,Materials Chemistry ,Humans ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Binding site ,Ligand molecule - Abstract
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences, and they are attractive anticancer drug targets. Understanding the three-dimensional interactions between a G-quadruplex and its ligand in solution is the key to discovering a drug lead. Hence, from crystallographic or NMR structures, molecular dynamics studies have been performed on six ligand-quadruplex complexes. BRACO-19, BSU6039, daunomycin, RHPS4, MMQ1, and TMPyP4 are the six ligands that bind to the G-quadruplex structures in the studies. Based on molecular dynamics simulations and a series of computational analyses, the results suggest that ions move away from the external G-quartet to let the ligand bind to the quadruplex in aqueous solution. The ligand binding can increase the stability of the Hoogseen hydrogen bonds within the G-quartet. However, the G-quartet binding site can only fit one ligand molecule. The ligand can form hydrogen bonds at the loop or flank of the quadruplex. However, not all the interactions will stabilize the ligand-quadruplex complex in aqueous solution. These findings can assist in the design of selective and potent G-quadruplex ligands.
- Published
- 2010
21. Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands
- Author
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Zhi-Shu Huang, Yan Ma, Shi-Liang Huang, Tian-Miao Ou, Jia-Heng Tan, Jin-Qiang Hou, and Lian-Quan Gu
- Subjects
Berberine ,Guanine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ligands ,G-quadruplex ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Side chain ,Humans ,heterocyclic compounds ,Telomerase ,Molecular Biology ,Aza Compounds ,Ligand ,Organic Chemistry ,Biological activity ,Telomere ,G-Quadruplexes ,chemistry ,Reverse Transcriptase Inhibitors ,Molecular Medicine ,DNA - 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.
- Published
- 2009
22. 9-Substituted berberine derivatives as G-quadruplex stabilizing ligands in telomeric DNA
- Author
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Wei-Bin Wu, Tian-Miao Ou, Zhi-Shu Huang, Jin-Lin Zhou, Ying-Yu Huang, Wan-Jin Zhang, Kwok Yin Wong, Lian-Quan Gu, and Yu-Jing Lu
- Subjects
Telomerase ,Berberine ,Guanine ,Stereochemistry ,Clinical Biochemistry ,Fluorescence spectrometry ,Pharmaceutical Science ,Ligands ,G-quadruplex ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cations ,Cell Line, Tumor ,Drug Discovery ,Humans ,Molecular Biology ,Molecular Structure ,Circular Dichroism ,Organic Chemistry ,Gene Amplification ,DNA ,Telomere ,Ligand (biochemistry) ,G-Quadruplexes ,chemistry ,Metals ,Molecular Medicine - Abstract
The interaction of berberine and its 9-substituted derivatives with human telomeric DNA d[G(3)(T(2)AG(3))(3)](telo21) has been investigated via CD spectroscopy, fluorescence spectroscopy, PCR-stop assay, competitive dialysis, and telomerase repeat amplification protocol (TRAP) assay. The results indicated that these semisynthesized compounds could induce and stabilize the formation of anti-parallel G-quadruplex of telomeric DNA in the presence or absence of metal cations. Compared with berberine, the 9-substituted derivatives exhibit stronger binding affinity with G-quadruplex and higher inhibitory activity for telomerase. Introduction of a side chain with proper length of methylene and terminal amino group to the 9-position of berberine would significantly strengthen the binding affinity with G-quadruplex, resulting in increasing inhibitory effects on the amplification of telo21 DNA and on the telomerase activity.
- Published
- 2007
23. Development of a highly sensitive fluorescent light-up probe for G-quadruplexes
- Author
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Rui-Jun Guo, Zhi-Shu Huang, Shuo-Bin Chen, Tian-Miao Ou, Ming-Hao Hu, and Jia-Heng Tan
- Subjects
Optical Phenomena ,Supramolecular chemistry ,Quantum yield ,Nanotechnology ,Molecular Dynamics Simulation ,G-quadruplex ,Biochemistry ,Analytical Chemistry ,Fluorescent light ,Limit of Detection ,Electrochemistry ,Environmental Chemistry ,Animals ,heterocyclic compounds ,Spectroscopy ,Fluorescent Dyes ,Detection limit ,Base Sequence ,Chemistry ,Imidazoles ,DNA ,Combinatorial chemistry ,Fluorescence ,G-Quadruplexes ,Spectrometry, Fluorescence ,Drug Design ,Nucleic acid ,Cattle ,Selectivity - Abstract
G-quadruplexes are higher-order nucleic acid structures that have attracted extensive attention because of their biological significance and potential applications in supramolecular chemistry. An ever-increasing interest in G-quadruplexes has promoted the development of selective and sensitive fluorescent probes as research tools for these structures. However, most current studies primarily focus on the improved selectivity of probes for G-quadruplexes. Their detection limits or ways to improve their detection limits are rarely described. In this study, a new set of di-substituted triarylimidazole fluorescent probes were designed and synthesized, with the aim of upgrading the detection limit of a lead triarylimidazole IZCM-1 for G-quadruplexes. Among these compounds, IZCM-7 was the most promising candidate. The limit of detection (LOD) value of IZCM-7 for the G-quadruplex was up to 3 nM in solution and up to 5 ng in a gel matrix. These values were significantly improved in comparison with those of IZCM-1. Further biophysical studies revealed that the fluorescence quantum yield and binding affinity of IZCM-7 for G-quadruplexes were markedly increased, and these two factors might be responsible for the significantly improved detection limit of IZCM-7. In addition, the sensitive and selective fluorescence performance of IZCM-7 for G-quadruplexes remained the same even in the presence of large amounts of non-G-quadruplex competitors, suggesting its promising application prospect.
- Published
- 2015
24. Identification of a selective G-quadruplex DNA binder using a multistep virtual screening approach
- Author
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Shuo-Bin Chen, Jia-Heng Tan, Jin-Qiang Hou, Leonard G. Luyt, Zhi-Shu Huang, Tian-Miao Ou, and Li-Peng Zan
- Subjects
Molecular Dynamics Simulation ,G-quadruplex ,Ligands ,Catalysis ,Proto-Oncogene Proteins c-myc ,Small Molecule Libraries ,chemistry.chemical_compound ,Materials Chemistry ,Fluorescence Resonance Energy Transfer ,heterocyclic compounds ,Luciferase ,Promoter Regions, Genetic ,Virtual screening ,Binding Sites ,Chemistry ,Metals and Alloys ,General Chemistry ,DNA ,Surface Plasmon Resonance ,Ligand (biochemistry) ,Combinatorial chemistry ,Small molecule ,Molecular biology ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,G-Quadruplexes ,Förster resonance energy transfer ,Ceramics and Composites ,Nucleic Acid Conformation ,Selectivity - Abstract
To efficiently identify small molecules binding to a G-quadruplex structure while avoiding binding to duplex DNA, we performed a multistep structure-based virtual screening by simultaneously taking into account G-quadruplex DNA and duplex DNA. Among the 13 compounds selected, one outstanding ligand shows significant selectivity for G-quadruplex binding as determined using SPR, FRET-based competition and luciferase activity assay.
- Published
- 2014
25. Development of a new colorimetric and red-emitting fluorescent dual probe for G-quadruplex nucleic acids
- Author
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Jin-wu Yan, Jia-Heng Tan, Tian-Miao Ou, Lian-Quan Gu, Wen-Jie Ye, Shuo-Bin Chen, Ding Li, Hui-Yun Liu, and Zhi-Shu Huang
- Subjects
Fluorophore ,Lung Neoplasms ,G-quadruplex ,DNA, Ribosomal ,Catalysis ,chemistry.chemical_compound ,Alkaloids ,Materials Chemistry ,Humans ,heterocyclic compounds ,Fluorescent Dyes ,Isaindigotone ,Molecular Structure ,Chemistry ,Metals and Alloys ,RNA-Binding Proteins ,General Chemistry ,DNA ,Phosphoproteins ,Fluorescence ,Combinatorial chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,G-Quadruplexes ,Visual detection ,Spectrometry, Fluorescence ,Ceramics and Composites ,Nucleic acid ,Dual probe ,Quinazolines ,Colorimetry ,Indicators and Reagents ,HeLa Cells - Abstract
A tailor-made colorimetric and red-emitting fluorescent dual probe for G-quadruplex nucleic acids was developed by incorporating a coumarin–hemicyanine fluorophore into an isaindigotone framework. The significant and distinct changes in both the color and fluorescence of this probe enable the label-free and visual detection of G-quadruplex structures.
- Published
- 2014
26. DNA G-quadruplex binders: a patent review
- Author
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Jia-Heng Tan, Zhi-Shu Huang, Lian-Quan Gu, Tian-Miao Ou, and Yi-Yong Yan
- Subjects
Pharmacology ,Genetics ,Macrocyclic Compounds ,DNA replication ,Promoter ,Antineoplastic Agents ,General Medicine ,Biology ,G-quadruplex ,Hydrocarbons, Aromatic ,Telomere ,G-Quadruplexes ,Patents as Topic ,chemistry.chemical_compound ,chemistry ,Drug Design ,Drug Discovery ,Humans ,heterocyclic compounds ,Human genome ,Indicators and Reagents ,Related gene ,Immunoglobulin Gene Rearrangement ,DNA - Abstract
DNA G-quadruplexes are four-stranded DNA structures and are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. G-quadruplex structures can play important roles, including in immunoglobulin gene rearrangements, DNA replication, gene transcription, and are viewed as valid therapeutic targets in human cancer diseases. Design of G-quadruplex binders that target these structures and regulate related gene functions through stabilization of these structures are emerging as an exciting new class of potential anticancer agents. Besides as drug candidate, DNA G-quadruplex binders can also serve as excellent probes, helping the further exploration of biological functions of G-quadruplex and early diagnosis of G-quadruplex-related disease.This review provides an overview of current knowledge on patents of DNA G-quadruplex binders from 2008 to 2013. Information is collected from an extensive search, covering Derwent Innovations Index, Espacenet, SciFinder, and Google patent search.With the accumulating evidence of G-quadruplex as an effective drug target, an increasing number of DNA G-quadruplex binders with diverse structural features were developed. These binders are either used as drug candidates targeting G-quadruplex, or as probes for diagnostic purpose in genomic study. This review would mainly focus on the patents published after 2008 (including 2008). In order to cover all the diverse structural types of DNA G-quadruplex binders, some patents published before 2008 would be mentioned as well.
- Published
- 2013
27. Synthesis and Evaluation of Quinazolone Derivatives as a New Class of c-KIT G-Quadruplex Binding Ligands
- Author
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Zhi-Shu Huang, Jia-Heng Tan, Shuo-Bin Chen, Jin-wu Yan, Chen-Xi Zhou, Xiao-Xiao Wang, Jin-Qiang Hou, Tian-Miao Ou, and Lian-Quan Gu
- Subjects
Dna duplex ,Stereochemistry ,Organic Chemistry ,Biology ,Bioinformatics ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Cell culture ,Transcription (biology) ,Drug Discovery ,heterocyclic compounds ,Selectivity ,Cytotoxicity ,Gene ,DNA ,G quadruplex binding - Abstract
The c-KIT G-quadruplex structures are a novel class of attractive targets for the treatment of gastrointestinal stromal tumor (GIST). Herein, a series of new quinazolone derivatives with the expansion of unfused aromatic ring system were designed and synthesized. Subsequent biophysical studies demonstrated that the derivatives with adaptive scaffold could effectively bind to and stabilize c-KIT G-quadruplexes with good selectivity against duplex DNA. More importantly, these ligands further inhibited the transcription and expression of c-KIT gene and exhibited significant cytotoxicity on the GIST cell line HGC-27. Overall, these quinazolone derivatives represent a new class of promising c-KIT G-quadruplex ligands. The experimental results have also reinforced the idea of inhibition of c-KIT expression through targeting c-KIT G-quadruplex DNA.
- Published
- 2013
28. The role of positive charges on G-quadruplex binding small molecules: learning from bisaryldiketene derivatives
- Author
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Tian-Miao Ou, Dan Peng, Siyuan Huang, Lian-Quan Gu, Zhi-Shu Huang, Qiu-Xia Shi, Jia-Heng Tan, Ding Li, and Shuo-Bin Chen
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Molecular model ,Stereochemistry ,Dna interaction ,Biophysics ,Alkylation ,Calorimetry ,Molecular Dynamics Simulation ,Ligands ,Biochemistry ,Small Molecule Libraries ,chemistry.chemical_compound ,Lactones ,Moiety ,heterocyclic compounds ,Molecular Biology ,G quadruplex binding ,Chemistry ,Circular Dichroism ,Rational design ,DNA ,Small molecule ,G-Quadruplexes ,Kinetics ,Thermodynamics ,Spectrophotometry, Ultraviolet - Abstract
Background G-quadruplexes are promising therapeutic targets for small molecules. In general, the introduction of steady positive charges through the in situ alkylation of nitrogen atoms within potential G-quadruplex ligands can significantly improve their quadruplex binding and stabilization abilities. However, our previous studies on bisaryldiketene derivatives showed that the derivative M4 , whose central piperidone moiety is quaternized, exhibits a poor G-quadruplex stabilization ability. Methods To clarify this unusual finding, CD, ITC, UV and NMR analyses were performed to determine the binding behaviors of M4 and its non-quaternized analog M2 to G-quadruplex DNA [d(TGGGT)] 4 . Molecular modeling approaches were also employed to help illustrate ligand–quadruplex DNA interactions. Results The CD melting and ITC analyses revealed that M2 exhibited much stronger stabilization and binding abilities to [d(TGGGT)] 4 compared to M4 . Moreover, the CD and ITC analyses in combination with UV, NMR and MD simulations revealed that M2 tended to be end-stacked on the G-quartet, whereas M4 tended to be bound in the groove region. Analysis of the electrostatic potential showed that the charged surface of M4 was more positive than that of M2 and other reported ligands that bind to the G-quadruplex via end-stacking interactions. Conclusions The results indicated that the different positively charged surfaces of M2 and M4 might be the key reason for their different binding modes. These different binding modes also lead to different binding affinities and stabilization abilities for [d(TGGGT)] 4 . General significance These results provide new clues for the rational design of G-quadruplex-binding small molecules with steady positive charges.
- Published
- 2013
29. Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II
- Author
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Lin-Kun An, Tian-Miao Ou, Zhi-Shu Huang, Lian-Quan Gu, Ming-Hao Hu, Pei-Fen Yao, Jia-Heng Tan, Shi-Tian Zhuo, Shi-Liang Huang, Chun-Yan Li, Shuo-Bin Chen, and Ding Li
- Subjects
Models, Molecular ,medicine.drug_class ,Stereochemistry ,Phenazine ,Antineoplastic Agents ,Apoptosis ,HL-60 Cells ,Cleavage (embryo) ,Biochemistry ,HeLa ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,medicine ,Structure–activity relationship ,Humans ,Topoisomerase II Inhibitors ,Physical and Theoretical Chemistry ,Cell Proliferation ,biology ,Dose-Response Relationship, Drug ,Topoisomerase ,Organic Chemistry ,DNA replication ,biology.organism_classification ,Recombinant Proteins ,DNA Topoisomerases, Type II ,chemistry ,DNA Topoisomerases, Type I ,biology.protein ,MCF-7 Cells ,Phenazines ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors ,DNA ,Topoisomerase inhibitor ,HeLa Cells - Abstract
Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1–10 μM on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure–activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I–DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells.
- Published
- 2013
30. Stabilization of G-quadruplex DNA by C-5-methyl-cytosine in bcl-2 promoter: implications for epigenetic regulation
- Author
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Lian-Quan Gu, Tian-Miao Ou, Yi-Yong Yan, Handan Xiang, Jia-Heng Tan, Zhi-Shu Huang, Ding Li, Jin-Qiang Hou, Jing Lin, and Yu-chao Gu
- Subjects
Models, Molecular ,Transcription, Genetic ,Bisulfite sequencing ,Biophysics ,Biology ,Nucleic Acid Denaturation ,Biochemistry ,Polymerase Chain Reaction ,Epigenesis, Genetic ,chemistry.chemical_compound ,Cytosine ,Epigenetics of physical exercise ,Fluorescence Resonance Energy Transfer ,Humans ,heterocyclic compounds ,Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Epigenomics ,Circular Dichroism ,Temperature ,Computational Biology ,Cell Biology ,Methylation ,DNA Methylation ,Molecular biology ,Genes, bcl-2 ,G-Quadruplexes ,chemistry ,CpG site ,DNA methylation ,CpG Islands ,DNA - Abstract
The C-5-methylation of cytosine in the CpG islands is an important pattern for epigenetic modification of gene, which plays a key role in regulating gene transcription. G-quadruplex is an unusual DNA secondary structure formed in G-rich regions and is identified as a transcription repressor in some oncogenes, such as c-myc and bcl-2. In the present study, the results from CD spectrum and FRET assay showed that the methylation of cytosine in the CpG islands could induce a conformational change of the G-quadruplex in the P1 promoter of bcl-2, and greatly increase the thermal-stability of this DNA oligomer. Moreover, the methylation of cytosine in the G-quadruplex could protect the structure from the disruption by the complementary strand, showing with the increasing ability to arrest the polymerase in PCR stop assay. This data indicated that the stabilization of the G-quadruplex structure in the CpG islands might be involved in the epigenetical transcriptional regulation for specific genes through the C-5-methylation modification pattern.
- Published
- 2012
31. Benzofuroquinoline derivatives had remarkable improvement of their selectivity for telomeric g-quadruplex DNA over duplex DNA upon introduction of peptidyl group
- Author
-
Tian-Miao Ou, Lian-Quan Gu, Jia-Heng Tan, Yi Long, Ding Li, Zhi-Shu Huang, Zeng Li, Long, Yi, Li, Zeng, Tan, Jia Heng, Ou, Tian Miao, Li, Ding, Gu, Lian Quan, and Huang, Zhi Shu
- Subjects
Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Circular dichroism ,Magnetic Resonance Spectroscopy ,Molecular model ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,G-quadruplex ,chemistry.chemical_compound ,Surface plasmon resonance ,Benzofurans ,DNA Primers ,Pharmacology ,benzofurans ,Base Sequence ,Circular Dichroism ,Organic Chemistry ,Surface Plasmon Resonance ,Telomere ,G-quadruplexes ,G-Quadruplexes ,Förster resonance energy transfer ,Biochemistry ,Cryptolepine ,chemistry ,Quinolines ,Biophysics ,DNA ,Biotechnology - Abstract
In order to improve the selectivity of 5-N-methyl quindoline (cryptolepine) derivatives as telomeric quadruplex binding ligands versus duplex DNA, a series of peptidyl-benzofuroquinoline (P-BFQ) conjugates (2a-2n) were designed and synthesized. Their interactions with telomeric quadruplex and duplex DNA were examined by using the fluorescence resonance energy transfer (FRET) melting assay, surface plasmon resonance (SPR), circular dichroism spectroscopy (CD), and molecular modeling studies. Introduction of a peptidyl group at 11-position of the aromatic benzofuroquinoline scaffold not only effectively increased its binding affinity, but also significantly improved its selectivity toward telomeric quadruplex versus duplex DNA. Combined with the data for their inhibitory effects on telomerase activity, their structure-activity relationships (SARs) studies showed that the types of amino acid residues and the length of the peptidyl side chains were important for the improvement of their interactions with the telomeric G-quadruplex. Long-term exposure of human cancer cells to 2c showed a remarkable cessation in population growth and cellular senescence phenotype, and accompanied by a shortening of the telomere length. Refereed/Peer-reviewed
- Published
- 2012
32. Disubstituted quinazoline derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA
- Author
-
Lian-Quan Gu, Zhi-Shu Huang, Tian-Miao Ou, Zeng Li, Jin-Hui He, Yi Long, Ding Li, Jia-Heng Tan, Li, Zeng, Tan, Jia Heng, He, Jin Hui, Long, Yi, Ou, Tian Miao, Li, Ding, Gu, Lian Quan, and Huang, Zhi Shu
- Subjects
Models, Molecular ,Circular dichroism ,Molecular model ,Stereochemistry ,interaction ,HL-60 Cells ,telomerase inhibition ,G-quadruplex ,Ligands ,chemistry.chemical_compound ,Drug Discovery ,Quinazoline ,Humans ,heterocyclic compounds ,Surface plasmon resonance ,Telomerase ,Telomere Shortening ,quinazoline derivatives ,Pharmacology ,Base Sequence ,Ligand ,Spectrum Analysis ,Organic Chemistry ,selectivity ,General Medicine ,DNA ,Telomere ,G-Quadruplexes ,G-quadruplex DNA ,Förster resonance energy transfer ,chemistry ,Quinazolines - Abstract
A series of 2,4-disubstituted quinazoline derivatives found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time.Their interactions with telomeric G-quadruplex DNA were evaluated by using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR), and molecular modeling. Our results showed that these derivatives could well recognize G-quadruplex and have high selectivity toward G-quadruplex over duplex DNA. The structure-activity relationships (SARs) study revealed that the disubstitution of quinazoline and the length of the amide side chain were important for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the quinazoline derivatives and their cellular effects were studied. Refereed/Peer-reviewed
- Published
- 2011
33. G-Quadruplex DNA and its Ligands in Anticancer Therapy
- Author
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Tian-Miao Ou, Lian-Quan Gu, Ding Li, Zhi-Shu Huang, and Jia-Heng Tan
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,G-quadruplex ,DNA - Published
- 2011
34. Effective detection and separation method for G-quadruplex DNA based on its specific precipitation with Mg(2+)
- Author
-
Jia-Heng Tan, Ding Li, Lian-Quan Gu, Jing Lin, Shi-Liang Huang, Zhi-Shu Huang, Yi-Yong Yan, and Tian-Miao Ou
- Subjects
Gel electrophoresis ,Chromatography ,Polymers and Plastics ,Precipitation (chemistry) ,Polymers ,Bioengineering ,DNA separation by silica adsorption ,G-quadruplex ,Nucleic acid secondary structure ,Biomaterials ,G-Quadruplexes ,chemistry.chemical_compound ,chemistry ,Microscopy, Electron, Transmission ,Materials Chemistry ,Biophysics ,Separation method ,Chemical Precipitation ,Nucleic Acid Conformation ,heterocyclic compounds ,Magnesium ,Magnesium ion ,DNA - Abstract
G-quadruplex is a type of DNA secondary structure formed by specific guanine-rich sequences. Because of their enrichment in functional genomic regions and their biological significance, G-quadruplexes are recognized as significant drug targets for cancer and other diseases. Here, we tested the precipitation efficiency of Mg(2+) for various DNA oligomers, including single-stranded, double-stranded, triplex, hairpin, i-motif, and some reported G-quadruplex DNA. It was found that Mg(2+) could specifically recognize and precipitate G-quadruplex DNA with a particularly high efficiency of close to 100% for G-quadruplex structures with parallel conformation, which provided an inexpensive and convenient method for detecting and separating G-quadruplex DNA from other DNA structures as well as identifying parallel G-quadruplex from other conformational G-quadruplexes. Further experiments with both CD and gel electrophoresis validated the effectiveness of this approach. The structure of the precipitate was characterized using transmission electron microscopy (TEM), and the observed linear precipitate suggested that a polymerization of G-quadruplex DNA was formed through π-π stacking of end to end by the unique large aromatic surface of G-quadruplex.
- Published
- 2010
35. Selective recognition of oncogene promoter G-quadruplexes by Mg2+
- Author
-
Zhi-Shu Huang, Tian-Miao Ou, Lian-Quan Gu, Yi-Yong Yan, Ding Li, Jing Lin, and Jia-Heng Tan
- Subjects
Response element ,Biophysics ,Electrophoretic Mobility Shift Assay ,Biology ,G-quadruplex ,Biochemistry ,chemistry.chemical_compound ,Fluorescence Resonance Energy Transfer ,Humans ,heterocyclic compounds ,Electrophoretic mobility shift assay ,Magnesium ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Regulation of gene expression ,Oncogene ,Base Sequence ,Circular Dichroism ,Cell Biology ,DNA ,Oncogenes ,Molecular biology ,G-Quadruplexes ,Gene Expression Regulation, Neoplastic ,chemistry ,Nucleic acid - Abstract
Mg(2+) is one of the most important cations in cells, affecting the structures and functions of the proteins and nucleic acids. It should be noted that Mg(2+) is indispensable in DNA transcription, where G-quadruplex is believed to be actively involved. Therefore, it is important to investigate the influence of Mg(2+) on G-quadruplex. Here we studied the effect of Mg(2+) on G-quadruplex DNA with CD, FRET, EMSA, and PCR-stop assay. We found that various G-quadruplexes could be differentiated through simultaneous addition of both K(+) and Mg(2+), which could be used for selective identification of G-quadruplexes in promoter oncogene but not in telomere. Mg(2+) at physiological relevant concentration not only greatly enhanced the thermostability of oncogene G-quadruplexes but also efficiently protected them from unfolding by their complementary strands, which revealed the great impact of Mg(2+) on the equilibrium between promoter G-quadruplex and duplex DNA. The PCR-stop assay further confirmed that Mg(2+) could affect gene transcription by stabilizing promoter G-quadruplex. The above studies were carried out for various G-quadruplexes of varying sequences in promoter oncogenes and telomeric region. Our results suggest that Mg(2+) may be a key regulator for G-quadruplexes of oncogene promoter, which can subsequently affect the expression of related genes.
- Published
- 2010
36. Bisaryldiketene derivatives: A new class of selective ligands for c-myc G-quadruplex DNA
- Author
-
Zhi-Shu Huang, Jia-Heng Tan, Lian-Quan Gu, Dan Peng, Shuo-Bin Chen, and Tian-Miao Ou
- Subjects
Stereochemistry ,Guanine ,Clinical Biochemistry ,Fluorescence spectrometry ,Pharmaceutical Science ,Calorimetry ,G-quadruplex ,Ligands ,Biochemistry ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Lactones ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,heterocyclic compounds ,Binding site ,Molecular Biology ,Quinolinium Compounds ,Organic Chemistry ,Nucleic acid sequence ,DNA ,Ligand (biochemistry) ,G-Quadruplexes ,chemistry ,Quinolines ,Molecular Medicine ,Thermodynamics ,Linker - Abstract
A series of bisaryldiketene derivatives were designed and synthesized as a new class of specific G-quadruplex ligands. The ligand-quadruplex interactions were further evaluated by FRET, ITC, and PCR stop assay. In contrast to most of the G-quadruplex ligands reported so far, which comprise an extended aromatic ring, these compounds are neither polycyclic nor macrocyclic, but have a non-aromatic and relative flexible linker between two quinoline moieties enabling the conformation of compounds to be flexible. Our results showed that these bisaryldiketene derivatives could selectively recognize G-quadruplex DNA rather than binding to duplex DNA. Moreover, they showed promising discrimination between different G-quadruplex DNA. The primary binding affinity of ligand M2 for c-myc G-quadruplex DNA was over 200 times larger than that for telomere G-quadruplex DNA.
- Published
- 2010
37. 9-N-Substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc
- Author
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Zhi-Shu Huang, Yan Ma, Lian-Quan Gu, Jin-Qiang Hou, Tian-Miao Ou, Jia-Heng Tan, and Yu-Jing Lu
- Subjects
Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Tertiary amine ,Berberine ,Guanine ,Clinical Biochemistry ,Molecular Sequence Data ,Genes, myc ,Pharmaceutical Science ,Down-Regulation ,Electrophoretic Mobility Shift Assay ,HL-60 Cells ,Cell Growth Processes ,G-quadruplex ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Transcription (biology) ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Humans ,heterocyclic compounds ,Electrophoretic mobility shift assay ,Promoter Regions, Genetic ,Molecular Biology ,Base Sequence ,Cell growth ,Reverse Transcriptase Polymerase Chain Reaction ,Circular Dichroism ,Organic Chemistry ,DNA ,G-Quadruplexes ,chemistry ,Molecular Medicine ,Thermodynamics - Abstract
A series of 9-N-substituted berberine derivatives (2a-j) were synthesized and evaluated as a new class of G-quadruplex binding ligands. G-quadruplex of DNA had been proven to be the transcription controller of human c-myc gene. The interaction of 9-N-substituted berberine derivatives with G-quadruplex DNA in c-myc was examined via EMSA, CD spectroscopy, FRET-melting method, PCR-stop assay, competitive dialysis, cell proliferation assay, and RT-PCR assay. The experiment results indicated that these derivatives could selectively induce and stabilize the formation of intramolecular parallel G-quadruplex in c-myc, which led to down-regulation of transcription of the c-myc in the HL60 lymphomas cell line. The related structure-activity relationships were also discussed.
- Published
- 2008
38. G-quadruplexes: targets in anticancer drug design
- Author
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Lian Quan Gu, Tian Miao Ou, Jia Heng Tan, Yu Jing Lu, Kwok Yin Wong, and Zhi Shu Huang
- Subjects
Models, Molecular ,Porphyrins ,Genes, myc ,Antineoplastic Agents ,Computational biology ,Pharmacology ,Biology ,G-quadruplex ,Ligands ,Biochemistry ,Genome ,Eukaryotic genome ,Drug Discovery ,Humans ,heterocyclic compounds ,General Pharmacology, Toxicology and Pharmaceutics ,Gene ,Calorimetry, Differential Scanning ,Genome, Human ,Organic Chemistry ,DNA ,Telomere ,Anticancer drug ,Genes, bcl-2 ,G-Quadruplexes ,Proto-Oncogene Proteins c-kit ,Drug Design ,Molecular Medicine ,Nucleic Acid Conformation - Abstract
G-quadruplexes are special secondary structures adopted in some guanine-rich DNA sequences. As guanine-rich sequences are present in important regions of the eukaryotic genome, such as telomeres and the regulatory regions of many genes, such structures may play important roles in the regulation of biological events in the body. G-quadruplexes have become valid targets for new anticancer drugs in the past few decades. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Nonetheless, the selectivity of this kind of antitumor compound has yet to be improved in order to suppress the side effects caused by nonselective binding. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of small-ligand binding to these structures should be understood clearly. Herein we provide a summary of published research that has set out to address the above problem to provide useful information on the design of small ligands that target G-quadruplexes. This review also covers research methodologies that have been developed to study the binding of ligands to G-quadruplexes.
- Published
- 2008
39. Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives
- Author
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Chi Zhang, Yuan Chen, Yu-Jing Lu, Tian-Miao Ou, Lian-Quan Gu, Jia-Heng Tan, Albert S. C. Chan, Xiao-Dong Wang, Zhi-Shu Huang, Dik-Lung Ma, Kwok Yin Wong, and Johnny Cheuk On Tang
- Subjects
Models, Molecular ,Guanine ,Indoles ,Molecular model ,Tertiary amine ,Stereochemistry ,Static Electricity ,Antineoplastic Agents ,G-quadruplex ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alkaloids ,Isomerism ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Humans ,heterocyclic compounds ,Nucleotide ,Promoter Regions, Genetic ,Cell Proliferation ,chemistry.chemical_classification ,Base Sequence ,Chemistry ,Circular Dichroism ,Promoter ,DNA ,Quinolines ,Molecular Medicine ,Nucleic Acid Conformation ,Thermodynamics ,Dialysis - Abstract
Stabilization of G-quadruplex structures in the promoter region of certain oncogenes is an emerging field in anticancer drug design. Human c-myc gene is one of these oncogenes, and G-quadruplexes have been proven to be the transcriptional controller of this gene. In the present study, the interaction of quindoline derivatives with G-quadruplexes in c-myc was investigated. The experimental results indicated that these derivatives have the ability to induce/stabilize the G-quadruplexes in c-myc, which lead to down-regulation of the c-myc in the Hep G2 cell line. It was found that derivatives with terminal amino groups in their side chains would selectively bind to the isomers with the double nucleotide loops in the absence of K+. Molecular modeling studies revealed the binding mode between the derivatives and the G-quadruplexes is end-stacking at the 3'-position, and the positively charged side chain on the quindoline derivatives may contribute to the selectivity to certain loop isomers of topological quadruplexes as well as the improved stabilization action.
- Published
- 2007
40. Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase
- Author
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Albert S. C. Chan, Lian Quan Gu, Jin Lin Zhou, Zhi Shu Huang, Cui Juan Du, Xian Zhang Bu, Junmin Zhou, Xiao Feng Zhu, Lin Ma, Yu Jing Lu, Tian Miao Ou, and Li Yueming
- Subjects
Circular dichroism ,Telomerase ,Indoles ,Guanine ,Stereochemistry ,Antineoplastic Agents ,Electrophoretic Mobility Shift Assay ,G-quadruplex ,Ligands ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alkaloids ,Drug Discovery ,Structure–activity relationship ,Humans ,heterocyclic compounds ,Electrophoretic mobility shift assay ,Circular Dichroism ,DNA ,Telomere ,chemistry ,Quinolines ,Molecular Medicine ,Thermodynamics ,Dialysis - Abstract
A new series of quindoline derivatives (4a-j) were designed and synthesized to develop novel and potent telomerase inhibitors. The interaction of the G-quadruplex of human telomere DNA with these newly designed molecules was examined via circular dichroism spectroscopy and electrophoretic mobility shift assay (EMSA). The selectivity between the quindoline derivative (4a) and G-quadruplex or duplex DNA was investigated by competition dialysis. These new compounds as inhibitors of telomerase were also investigated through the utilization of modified telomerase repeat amplification protocol (TRAP) assay. The results revealed that the introduction of electron-donating groups such as substituted amino groups at the C-11 position of quindoline significantly improved the inhibitory effect on telomerase activity ((Tel)IC50 > 138 microM for quindoline, 0.44-12.3 microM for quindoline derivatives 4a-j). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into quadruplex.
- Published
- 2005
41. Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA
- Author
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Lian-Quan Gu, Tian-Miao Ou, Jin-Qiang Hou, Wei-Bin Wu, Zhi-Shu Huang, Shi-Liang Huang, Jia-Heng Tan, Ding Li, and Shu-Han Chen
- Subjects
Models, Molecular ,Circular dichroism ,Molecular model ,Cell Survival ,Stereochemistry ,Ligands ,G-quadruplex ,Biochemistry ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Benzopyrans ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Surface plasmon resonance ,Telomerase ,Ligand ,Organic Chemistry ,Telomere ,G-Quadruplexes ,Pyrimidines ,Förster resonance energy transfer ,chemistry ,Selectivity ,DNA - Abstract
A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.
- Published
- 2011
42. Impact of planarity of unfused aromatic molecules on G-quadruplex binding: Learning from isaindigotone derivatives
- Author
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Jia-Heng Tan, Shuo-Bin Chen, Jin-Qiang Hou, Shu-Han Chen, Hai-Bin Luo, Lian-Quan Gu, Tian-Miao Ou, Jin-wu Yan, Xiao-Xiao Wang, Zhi-Shu Huang, Siyuan Huang, and Ding Li
- Subjects
Models, Molecular ,Circular dichroism ,Binding Sites ,Magnetic Resonance Spectroscopy ,Molecular model ,Stereochemistry ,Chemistry ,Circular Dichroism ,Organic Chemistry ,Binding energy ,DNA ,Ligand (biochemistry) ,Biochemistry ,Small molecule ,Planarity testing ,G-Quadruplexes ,Molecular dynamics ,Alkaloids ,Fluorescence Resonance Energy Transfer ,Quinazolines ,Humans ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Binding site - Abstract
G-quadruplex structures are a new class of attractive targets for DNA-interactive anticancer agents. The primary building block of this structure is the G-quartet, which is composed of four coplanar guanines and serves as the major binding site for small molecules. NMR studies and molecular dynamics simulations have suggested that the planarity of G-quartet surface has been highly dynamic in solution. To better investigate how the planarity of unfused aromatic ligand impacts on its quadruplex binding properties, a variety of planarity controllable isaindigotone derivatives were designed and synthesized. The interaction of G-quadruplex DNA with these designed ligands was systematically explored using a series of biophysical studies. The FRET-melting, SPR, and CD spectroscopy results showed that reducing the planarity of their unfused aromatic core resulted in their decreased binding affinity and stabilization ability for G-quadruplex. NMR studies also suggested that these compounds could stack on the G-quartet surface. Such results are in parallel with subsequent molecular modeling studies. A detailed binding energy analysis indicated that van der Waals energy (ΔE(vdw)) and entropy (TΔS) are responsible for their decreased quadruplex binding and stabilization effect. All these results provided insight information about how quadruplex recognition could be controlled by adjusting the planarity of ligands, which shed light on further development of unfused aromatic molecules as optimal G-quadruplex binding ligands.
- Published
- 2011
43. Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response.
- Author
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Tong Che, Shuo-Bin Chen, Jia-Li Tu, Bo Wang, Yu-Qing Wang, Yan Zhang, Jing Wang, Zeng-Qing Wang, Ze-Peng Zhang, Tian-Miao Ou, Yong Zhao, Jia-Heng Tan, and Zhi-Shu Huang
- Subjects
- *
DNA , *ANTINEOPLASTIC agents - Abstract
Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
44. Development of a Universal Colorimetric Indicator for G-Quadruplex Structures by the Fusion of Thiazole Orange and Isaindigotone Skeleton.
- Author
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Jin-Wu Yan, Wen-Jie Ye, Shuo-Bin Chen, Wei-Bm Wu, Jin-Ojang Hou, Tian-Miao Ou, Jia-Heng Tan, Ding Li, Lian-Quan Gu, and Zhi-Shu Huang
- Subjects
- *
COLORIMETRY , *QUADRUPLEX nucleic acids , *THIAZOLES , *MONOMERS , *CHEMICAL models , *FUSION (Phase transformation) , *DNA - Abstract
The rapid and convenient method for identification of all kinds of G-quadruplex is highly desirable. In the present study, a novel colorimetric indicator for a vast variety of G-quadruplex was designed and synthesized on the basis of thiazole orange and isaindigotone skeleton. Its distinct color change enables label-free visual detection of G-quadruplexes, which is due to the disassembly of dye H-aggregates to monomers. This specific detection of G-quadruplex arises from its end-stacking interaction with G-quartet. On the basis of this universal indicator, a facile approach for large-scale identification of G-quadruplex was developed. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
45. New Insights into the Structures of LigandâQuadruplex Complexes from Molecular Dynamics Simulations.
- Author
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Jin-Qiang Hou, Shuo-Bin Chen, Jia-Heng Tan, Tian-Miao Ou, Hai-Bin Luo, Ding Li, Jun Xu, Lian-Quan Gu, and Zhi-Shu Huang
- Subjects
- *
QUADRUPLEX nucleic acids , *LIGANDS (Chemistry) , *MOLECULAR dynamics , *SIMULATION methods & models , *DNA , *RNA , *ANTINEOPLASTIC agents , *CRYSTALLOGRAPHY , *NUCLEAR magnetic resonance - Abstract
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences, and they are attractive anticancer drug targets. Understanding the three-dimensional interactions between a G-quadruplex and its ligand in solution is the key to discovering a drug lead. Hence, from crystallographic or NMR structures, molecular dynamics studies have been performed on six ligandâquadruplex complexes. BRACO-19, BSU6039, daunomycin, RHPS4, MMQ1, and TMPyP4 are the six ligands that bind to the G-quadruplex structures in the studies. Based on molecular dynamics simulations and a series of computational analyses, the results suggest that ions move away from the external G-quartet to let the ligand bind to the quadruplex in aqueous solution. The ligand binding can increase the stability of the Hoogseen hydrogen bonds within the G-quartet. However, the G-quartet binding site can only fit one ligand molecule. The ligand can form hydrogen bonds at the loop or flank of the quadruplex. However, not all the interactions will stabilize the ligandâquadruplex complex in aqueous solution. These findings can assist in the design of selective and potent G-quadruplex ligands. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
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