67 results on '"Jia-Heng Tan"'
Search Results
2. Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma
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Xiu-Cai Chen, Gui-Xue Tang, Jing Dai, Le-Tian Dai, Tian-Ying Wu, Wen-Wei Li, Tian-Miao Ou, Zhi-Shu Huang, Jia-Heng Tan, and Shuo-Bin Chen
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Drug Discovery ,Molecular Medicine - Published
- 2023
3. Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex
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Mao-Lin Li, Jing-Mei Yuan, Hao Yuan, Bi-Han Wu, Shi-Liang Huang, Qing-Jiang Li, Tian-Miao Ou, Hong-Gen Wang, Jia-Heng Tan, Ding Li, Shuo-Bin Chen, and Zhi-Shu Huang
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Drug Discovery ,Molecular Medicine - Published
- 2022
4. Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer
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Xin-Chen Jiang, Fang-Hai Tu, Li-Yuan Wei, Bo-Zheng Wang, Hao Yuan, Jing-Mei Yuan, Yong Rao, Shi-Liang Huang, Qing-Jiang Li, Tian-Miao Ou, Hong-Gen Wang, Jia-Heng Tan, Shuo-Bin Chen, and Zhi-Shu Huang
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Histone Deacetylase Inhibitors ,Zinc ,Cell Line, Tumor ,Drug Discovery ,Humans ,Molecular Medicine ,Antineoplastic Agents ,Apoptosis ,Triple Negative Breast Neoplasms ,DNA ,Xenograft Model Antitumor Assays ,Histone Deacetylases ,Cell Proliferation - Abstract
The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (
- Published
- 2022
5. Development of a Highly Selective and Sensitive Fluorescent Probe for Imaging RNA Dynamics in Live Cells
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Lan Fang, Wen Shao, Shu-Tang Zeng, Gui-Xue Tang, Jia-Tong Yan, Shuo-Bin Chen, Zhi-Shu Huang, Jia-Heng Tan, and Xiu-Cai Chen
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RNA ,RNA granules ,small molecule ,fluorescent probe ,dynamics ,cell imaging ,Chemistry (miscellaneous) ,Organic Chemistry ,Drug Discovery ,Molecular Medicine ,Pharmaceutical Science ,RNA Probes ,Physical and Theoretical Chemistry ,Analytical Chemistry ,Fluorescent Dyes ,Molecular Imaging - Abstract
RNA imaging is of great importance for understanding its complex spatiotemporal dynamics and cellular functions. Considerable effort has been devoted to the development of small-molecule fluorescent probes for RNA imaging. However, most of the reported studies have mainly focused on improving the photostability, permeability, long emission wavelength, and compatibility with live-cell imaging of RNA probes. Less attention has been paid to the selectivity and detection limit of this class of probes. Highly selective and sensitive RNA probes are still rarely available. In this study, a new set of styryl probes were designed and synthesized, with the aim of upgrading the detection limit and maintaining the selectivity of a lead probe QUID−1 for RNA. Among these newly synthesized compounds, QUID−2 was the most promising candidate. The limit of detection (LOD) value of QUID−2 for the RNA was up to 1.8 ng/mL in solution. This property was significantly improved in comparison with that of QUID−1. Further spectroscopy and cell imaging studies demonstrated the advantages of QUID−2 over a commercially available RNA staining probe, SYTO RNASelect, for highly selective and sensitive RNA imaging. In addition, QUID−2 exhibited excellent photostability and low cytotoxicity. Using QUID−2, the global dynamics of RNA were revealed in live cells. More importantly, QUID−2 was found to be potentially applicable for detecting RNA granules in live cells. Collectively, our work provides an ideal probe for RNA imaging. We anticipate that this powerful tool may create new opportunities to investigate the underlying roles of RNA and RNA granules in live cells.
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- 2022
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6. Design, synthesis and evaluation of N3-substituted quinazolinone derivatives as potential Bloom's Syndrome protein (BLM) helicase inhibitor for sensitization treatment of colorectal cancer
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Jia-Li Tu, Bi-Han Wu, Heng-Bo Wu, Jia-En Wang, Zi-Lin Zhang, Kun-Yu Gao, Lu-Xuan Zhang, Qin-Rui Chen, Ying-Chen Zhou, Jia-Heng Tan, Zhi-Shu Huang, and Shuo-Bin Chen
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Pharmacology ,Organic Chemistry ,Drug Discovery ,General Medicine - Abstract
The homologous recombination repair (HRR) pathway is critical for repairing double-strand breaks (DSB). Inhibition of the HRR pathway is usually considered a promising strategy for anticancer therapy. The Bloom's Syndrome Protein (BLM), a DNA helicase, is essential for promoting the HRR pathway. Previously, we discovered quinazolinone derivative 9h as a potential BLM inhibitor, which suppressed the proliferation of colorectal cancer (CRC) cell HCT116. Herein, a new series of quinazolinone derivatives with N3-substitution was designed and synthesized to improve the anticancer activity and explore the structure-activity relationship (SAR). After evaluating their BLM inhibitory activity, the SAR was discussed, leading to identifying compound 21 as a promising BLM inhibitor. 21 exhibited the potent BLM-dependent cytotoxicity against the CRC cells but weak against normal cells. Further evaluation revealed that 21 could disrupt the HRR level while inhibiting BLM located on the DSB site and trigger DNA damage in the CRC cells. This compound effectively suppressed the proliferation and invasion of CRC cells, along with cell cycle arrest and apoptosis. Consequently, 21 might be a promising candidate for treating CRC, and the BLM might be a new potential therapeutic target for CRC.
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- 2022
7. Benzoselenazolium-based hemicyanine dye for G-Quadruplex detection
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Zhang-Chi Li, Tian-Ying Wu, Shu-Tang Zeng, Lan Fang, Jun-Xin Mao, Shuo-Bin Chen, Zhi-Shu Huang, Xiu-Cai Chen, and Jia-Heng Tan
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G-Quadruplexes ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Humans ,Carbocyanines ,Molecular Biology ,Biochemistry ,Fluorescent Dyes ,HeLa Cells - Abstract
Benzothiazolium and benzoxazolium are common groups for the construction of hemicyanine dyes; however, their isosteric analogue benzoselenazolium have rarely been studied. Here, we report the development of the first benzoselenazolium-based hemicyanine dye for the selective detection of G-quadruplexes. This molecule, SEMA-1, was validated as a red-emitting and activatable fluorescent probe whose fluorescence would only be activated in the presence of G-quadruplexes in buffer solution. Consistent with this, SEMA-1 was found to accumulate in nucleoli and could be used to detect the high abundance of nucleolar rDNA and rRNA G-quadruplexes in fixed HeLa cells. On the other hand, due to the retained mitochondrial membrane potential in live HeLa cells, SEMA-1 was captured by mitochondria and had the potential to detect the mitochondrial G-quadruplexes. Collectively, this work demonstrates the value of developing G-quadruplex-specific fluorescent probes from novel benzoselenazolium-based hemicyanine scaffold.
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- 2022
8. Fluorescent Quinolinium Derivative as Novel Mitochondria Probe and Function Modulator by Targeting Mitochondrial RNA
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Bo-Zheng Wang, Ying-Chen Zhou, Yu-Wei Lin, Xiu-Cai Chen, Ze-Yi Yu, Yao-Hao Xu, Jia-Heng Tan, Zhi-Shu Huang, and Shuo-Bin Chen
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Chemistry (miscellaneous) ,Organic Chemistry ,Drug Discovery ,Molecular Medicine ,Pharmaceutical Science ,Physical and Theoretical Chemistry ,RNA fluorescent probe ,OXPHOS inhibitor ,mitochondrial RNA ,anticancer ,Analytical Chemistry - Abstract
Mitochondria have a crucial role in regulating energy metabolism and their dysfunction has been linked to tumorigenesis. Cancer diagnosis and intervention have a great interest in the development of new agents that target biomolecules within mitochondria. However, monitoring and modulating mitochondria RNA (mtRNA), an essential component in mitochondria, in cells is challenging due to limited functional research and the absence of targeting agents. In this study, we designed and synthesized a fluorescent quinolinium derivative, QUCO-1, which actively lit up with mtRNA in both normal and cancer cells in vitro. Additionally, we evaluated the function of QUCO-1 as an mtRNA ligand and found that it effectively induced severe mitochondrial dysfunction and OXPHOS inhibition in RKO colorectal cancer cells. Treatment with QUCO-1 resulted in apoptosis, cell cycle blockage at the G2/M phase, and the effective inhibition of cell proliferation. Our findings suggest that QUCO-1 has great potential as a promising probe and therapeutic agent for mtRNA, with the potential for treating colorectal cancer.
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- 2023
9. 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
10. Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders
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Yao-Hao Xu, Zhi-Shu Huang, Tian-Miao Ou, Zhao Xu, Qingjiang Li, Hong Yu, Yong Rao, Shi-Liang Huang, Bing-Bing Song, Chan Li, Guo-Ping Zhong, Qin-Qin Song, Honggen Wang, Jia-Heng Tan, Shuo-Bin Chen, Yu-Tao Hu, and Ji-Ming Ye
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Male ,Cell ,Pharmacology ,Diet, High-Fat ,01 natural sciences ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Metabolic Diseases ,3T3-L1 Cells ,Drug Discovery ,medicine ,Animals ,Obesity ,Protein kinase A ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Metabolic disorder ,AMPK ,Cell Differentiation ,General Medicine ,medicine.disease ,0104 chemical sciences ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cholesterol ,Mitochondrial biogenesis ,Toxicity ,Microsome ,Anti-Obesity Agents - Abstract
Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC50 = 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders.
- Published
- 2019
11. Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction
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Zhi-Shu Huang, Lian-Quan Gu, Yu-Qing Wang, Jia-Heng Tan, Chan Shan, Qi-Kun Yin, Chen-Xi Wang, Tian-Miao Ou, Ding Li, Zhou-Li Huang, and Shuo-Bin Chen
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,Transcription, Genetic ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Ligands ,G-quadruplex ,Proto-Oncogene Proteins c-myc ,Structure-Activity Relationship ,03 medical and health sciences ,Transcription (biology) ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Pyrroles ,Promoter Regions, Genetic ,Gene ,Cell Proliferation ,Quinazolinones ,Mice, Inbred BALB C ,Chemistry ,NM23 Nucleoside Diphosphate Kinases ,G1 Phase Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,Molecular biology ,Small molecule ,Cell biology ,G-Quadruplexes ,Molecular Docking Simulation ,030104 developmental biology ,Design synthesis ,Doxorubicin ,Drug Design ,Quinazolines ,Molecular Medicine ,Tumor growth inhibition - Abstract
c-MYC is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate c-MYC transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit c-MYC transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating c-MYC ( J. Med. Chem. 2017 , 60 , 1292 - 1308 ). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound 37 showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated c-MYC transcription. Furthermore, 37 induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate c-MYC transcription for the development of selective anticancer drugs.
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- 2017
12. Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry
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Lian-Quan Gu, Qi Zhang, Shi-Ke Wang, Wang Peng, Zhi-Shu Huang, Xiao-Xuan Su, Tian-Miao Ou, Guo-Tao Kuang, De-Ying Zeng, Ming-Hao Hu, Shu-Ling Lin, Honggen Wang, and Jia-Heng Tan
- Subjects
Models, Molecular ,0301 basic medicine ,Stereochemistry ,Triazole ,Down-Regulation ,Mice, Nude ,Alkyne ,Antineoplastic Agents ,Quinolones ,G-quadruplex ,Cell Line ,Proto-Oncogene Proteins c-myc ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,heterocyclic compounds ,Cell Proliferation ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,Neoplasms, Experimental ,Triazoles ,Combinatorial chemistry ,G-Quadruplexes ,030104 developmental biology ,chemistry ,Click chemistry ,Nucleic acid ,Thermodynamics ,Molecular Medicine ,Click Chemistry ,Azide ,Drug Screening Assays, Antitumor - Abstract
The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks. The selectivity toward c-myc G-quadruplex DNA of these novel T-BFQs was significantly improved, together with an obvious increase on binding affinity. Further cellular and in vivo experiments indicated that the T-BFQs showed inhibitory activity on tumor cells' proliferation, presumably through the down-regulation of transcription of c-myc gene. Our findings broadened the modification strategies of specific G-quadruplex stabilizers.
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- 2017
13. Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents
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Xiao-Qin Wang, Shu-Ling Lin, Qi Zhang, Shi-Ke Wang, Jia-Heng Tan, Zhi-Shu Huang, Yue Wu, Tian-Miao Ou, Hui-Yun Liu, and Guo-Tao Kuang
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0301 basic medicine ,endocrine system ,Angiogenesis ,medicine.medical_treatment ,Mice, Nude ,Antineoplastic Agents ,medicine.disease_cause ,Bioinformatics ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Eukaryotic translation ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Cell Proliferation ,Mice, Inbred BALB C ,Messenger RNA ,Dose-Response Relationship, Drug ,Vascular Endothelial Growth Factors ,Chemistry ,Growth factor ,Mammary Neoplasms, Experimental ,Translation (biology) ,Cell biology ,Vascular endothelial growth factor ,030104 developmental biology ,Tumor progression ,MCF-7 Cells ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor ,Carcinogenesis - Abstract
Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated regions (5'-UTR) of hVEGF-A mRNA can form a "switchable" RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure. The results of cellular experiments revealed that compound 1 down-regulated hVEGF-A translation and significantly impeded tumor cells migration. We also found that compound 1 exhibited tumor-inhibiting activity in MCF-7 xenograft tumors, which might be related to its ability to reduce hVEGF expression. These findings present a new strategy of hVEGF-A translational control in which small molecules interact with G-quadruplex structure in the 5'UTR.
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- 2017
14. 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
15. Dimeric aryl-substituted imidazoles may inhibit ALT cancer by targeting the multimeric G-quadruplex in telomere
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Ming-Hao Hu, Jia-Heng Tan, Bin Liu, and Xiao-Tong Lin
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Telomerase ,Cell cycle checkpoint ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,G-quadruplex ,01 natural sciences ,03 medical and health sciences ,Structure-Activity Relationship ,Transcription (biology) ,Cell Line, Tumor ,Drug Discovery ,Humans ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Cell growth ,Chemistry ,Organic Chemistry ,Cell Cycle ,Imidazoles ,General Medicine ,Telomere ,0104 chemical sciences ,G-Quadruplexes ,Cancer cell ,Cancer research ,Drug Screening Assays, Antitumor - Abstract
In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4.
- Published
- 2019
16. 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
- Subjects
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.
- Published
- 2019
17. A colorimetric and fluorescent turn-on probe for carbon monoxide and imaging in living cells
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Zhong-yong Xu, Lei Zhang, Jin-wu Yan, Jing Li, Pei-Fen Yao, and Jia-Heng Tan
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Detection limit ,010405 organic chemistry ,Specific detection ,Organic Chemistry ,Phosphate buffered saline ,Living cell ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Biochemistry ,Fluorescence ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Dual probe ,Naked eye ,Carbon monoxide - Abstract
A colorimetric and fluorescent dual probe for CO is designed and synthesized. The probe is capable of sensitive and specific detection of CO with naked-eye through colorimetric assay in phosphate buffer from colorless to yellow, which also features 75-fold turn-on fluorescence enhancement upon exciting at 480 nm with the detection limit of 26.3 nM. The probe shows great potential for sensing intracellular CO without the interference in living cell imaging. On the other hand, the probe could also be utilized as an efficient and convenient visual indicator for CO gas in air by naked eyes.
- Published
- 2016
18. Design, Synthesis, and Evaluation of Novel p-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex
- Author
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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.
- Published
- 2018
19. 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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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
- Subjects
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.
- Published
- 2018
20. Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex
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Ming-Hao Hu, Tian-Miao Ou, Ze-Yi Yu, Lu-Ni Hu, Shuo-Bin Chen, Yu-Qing Wang, Jia-Heng Tan, and Zhi-Shu Huang
- Subjects
0301 basic medicine ,Models, Molecular ,Cell cycle checkpoint ,Carbazoles ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,G-quadruplex ,Ligands ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Transcription (biology) ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,heterocyclic compounds ,Promoter Regions, Genetic ,Tumor Stem Cell Assay ,Mice, Inbred BALB C ,Oncogene ,Drug discovery ,Cell growth ,Chemistry ,Imidazoles ,Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,Cell biology ,G-Quadruplexes ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor ,Intracellular ,Cell Division - Abstract
Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.
- Published
- 2018
21. Natural Alkaloids and Heterocycles as G-Quadruplex Ligands and Potential Anticancer Agents
- Author
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Yu-Qing Wang, Zhi-Shu Huang, Shuo-Bin Chen, Zhou-Li Huang, Tong Che, and Jia-Heng Tan
- Subjects
0301 basic medicine ,Untranslated region ,drug design ,Pharmaceutical Science ,Antineoplastic Agents ,Computational biology ,Review ,G-quadruplex ,Ligands ,Analytical Chemistry ,Transcriptome ,lcsh:QD241-441 ,03 medical and health sciences ,anticancer agents ,Structure-Activity Relationship ,Alkaloids ,lcsh:Organic chemistry ,Heterocyclic Compounds ,Drug Discovery ,Humans ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Promoter Regions, Genetic ,Biological Products ,Oncogene ,Chemistry ,Organic Chemistry ,Oncogenes ,Telomere ,G-Quadruplexes ,030104 developmental biology ,Chemistry (miscellaneous) ,Replication Initiation ,natural alkaloids ,Nucleic acid ,Molecular Medicine ,RNA ,Human genome - Abstract
G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are found to be associated with cancer, and thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this mini review, we summarize recent advances made by our lab in the study of G-quadruplex-targeted natural alkaloids and their derivatives toward the development of potential anticancer agents.
- Published
- 2018
22. Biological Function and Medicinal Research Significance of G-Quadruplex Interactive Proteins
- Author
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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
- Subjects
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
23. Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives
- Author
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Zhi-Shu Huang, Yun-Xia Xiong, and Jia-Heng Tan
- Subjects
Pharmacology ,Untranslated region ,Stereochemistry ,Organic Chemistry ,RNA ,DNA ,General Medicine ,G-quadruplex ,Small molecule ,G-Quadruplexes ,chemistry.chemical_compound ,Alkaloids ,Biochemistry ,chemistry ,Drug Design ,Drug Discovery ,Nucleic acid ,Animals ,Humans ,heterocyclic compounds ,Human genome ,Ribosomal DNA - Abstract
G-Quadruplex nucleic acids or G-quadruplexes (G4s) are four-stranded DNA or RNA secondary structures that are formed in guanine-rich sequences. They are widely distributed in functional regions of the human genome, such as telomeres, ribosomal DNA (rDNA), transcription start sites, promoter regions and untranslated regions of mRNA, suggesting that G-quadruplex structures may play a pivotal role in the control of a variety of cellular processes. G-Quadruplexes are viewed as valid therapeutic targets in human cancer diseases. Small molecules, from naturally occurring to synthetic, are exploited to specifically target G-quadruplexes and have proven to be a new class of anticancer agents. Notably, alkaloids are an important source of G-quadruplex ligands and have significant bioactivities in anticancer therapy. In this review, the authors provide a brief, up-to-date summary of heterocyclic alkaloids and their derivatives targeting G-quadruplexes.
- Published
- 2015
24. Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex
- Author
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Chan Shan, Jin-wu Yan, Ding Li, Ai-Chun Chen, Jia-Heng Tan, Zhou-Li Huang, Zhi-Shu Huang, Tian-Miao Ou, Lian-Quan Gu, Tong Che, Pei-Fen Yao, and Yu-Qing Wang
- Subjects
0301 basic medicine ,Transcriptional Activation ,Transcription, Genetic ,Down-Regulation ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,Apoptosis ,G-quadruplex ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,Alkaloids ,Transcription (biology) ,Cell Line, Tumor ,Drug Discovery ,Transcriptional regulation ,Humans ,heterocyclic compounds ,Regulation of gene expression ,Oncogene ,Chemistry ,Cell Cycle ,Promoter ,Cell cycle ,NM23 Nucleoside Diphosphate Kinases ,Molecular biology ,Cell biology ,G-Quadruplexes ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Drug Design ,Quinazolines ,Molecular Medicine ,Female - Abstract
Transcriptional control of c-myc oncogene is an important strategy for antitumor drug design. G-quadruplexes in the promoter region have been proven to be the transcriptional down-regulator of this gene. The transcriptional factor NM23-H2 can reactivate c-myc transcription by unwinding the G-quadruplex structure. Thus, down-regulation of c-myc transcription via disrupting G-quadruplex-NM23-H2 interaction might be a potential approach for cancer therapy. Here, a series of new isaindigotone derivatives were designed and synthesized based on our previous study. The abilities of these derivatives on interacting with G-quadruplexes or NM23-H2, and disrupting G-quadruplex-NM23-H2 interaction were evaluated. Among these derivatives, 19d and 22d showed remarkable abilities on disrupting G-quadruplex-NM23-H2 interaction. They exhibited significant effects on c-myc-relating processes in SiHa cells, including inhibiting the transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle. Our findings provided the basis for the anticancer strategy based on c-myc transcriptional regulation via small molecules disrupting G-quadruplex-protein interaction.
- Published
- 2017
25. β-Biguanidinium-cyclodextrin: a supramolecular mimic of mitochondrial ADP/ATP carrier protein
- Author
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Liang-Nian Ji, Jia-Heng Tan, Gao-Feng Liu, Meng Zhao, Zhi-Shu Huang, Huo-Yan Chen, and Zong-Wan Mao
- Subjects
chemistry.chemical_classification ,Cyclodextrin ,Arginine ,Stereochemistry ,Organic Chemistry ,Adenylate kinase ,Isothermal titration calorimetry ,Biochemistry ,Crystallography ,chemistry ,Docking (molecular) ,Drug Discovery ,Moiety ,Titration ,Nucleotide - Abstract
We reported a novel mono-β-cyclodextrin derivative, mono-6-deoxy-6-biguanidino-β-cyclodextrin ( β-biGCD ), which was investigated as a mimic of ADP/ATP carrier (AAC). Its affinity toward AMP, ADP, and ATP was evaluated by means of isothermal titration calorimetry (ITC). The association constants ( K a ) of β-biGCD binding to AMP, ADP, and ATP were determined to be (1.07±0.04)×10 6 , (5.86±0.02)×10 6 , and (4.33±0.06)×10 6 L mol −1 , respectively, which were 100-fold higher than mono-guanidino-β-cyclodextrin (ca. 10 4 L mol −1 ). UV spectroscopic titrations further confirmed the above results. The interaction between β-biGCD and nucleotides was probed by docking simulation. These results reveal that the biguanidinium moiety mimics the arginine residues of mitochondrial AAC protein.
- Published
- 2014
26. Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment
- Author
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Tian-Miao Ou, Chun-Li Xia, Shi-Liang Huang, Zhen-Quan Liu, Honggen Wang, Zhi-Shu Huang, Jia-Qiang Wu, Jia-Heng Tan, Ning Wang, Ding Li, and Qian-Liang Guo
- Subjects
0301 basic medicine ,Programmed cell death ,Antioxidant ,medicine.medical_treatment ,01 natural sciences ,Antioxidants ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Intragastric administration ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Pharmacology ,Amyloid beta-Peptides ,Cell Death ,010405 organic chemistry ,Organic Chemistry ,Quinoline ,Biological activity ,General Medicine ,Glutathione ,0104 chemical sciences ,030104 developmental biology ,Alzheimer's disease treatment ,chemistry ,Biochemistry ,Design synthesis ,Blood-Brain Barrier ,Drug Design ,Quinolines ,Cholinesterase Inhibitors ,Reactive Oxygen Species - Abstract
A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349–361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.
- Published
- 2016
27. Facile syntheses of disubstituted bis(vinylquinolinium)benzene derivatives as G-quadruplex DNA binders
- Author
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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
- Subjects
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
28. New quinazoline derivatives for telomeric G-quadruplex DNA: Effects of an added phenyl group on quadruplex binding ability
- Author
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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
- Subjects
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
29. New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA
- Author
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Zhi-Shu Huang, Hai-Bin Luo, Shuo-Bin Chen, Lian-Quan Gu, Ding Li, Jin-Qiang Hou, and Jia-Heng Tan
- Subjects
Flexibility (engineering) ,Principal Component Analysis ,Ligand ,Stereochemistry ,Chemistry ,Rational design ,Drug design ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Ligands ,G-quadruplex ,Combinatorial chemistry ,Small molecule ,Computer Science Applications ,G-Quadruplexes ,Molecular dynamics ,chemistry.chemical_compound ,Models, Chemical ,Drug Discovery ,heterocyclic compounds ,Physical and Theoretical Chemistry ,DNA - Abstract
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.
- Published
- 2012
30. Design, synthesis and biological evaluation of 4-anilinoquinazoline derivatives as new c-myc G-quadruplex ligands
- Author
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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
- Subjects
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
31. Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres
- Author
-
Qi Zhao, Ding Li, Zhi-Shu Huang, Yue Wu, Lian-Quan Gu, Jin-Hui He, Yuanlong Ge, Hui-Yun Liu, Yun-Xia Xiong, Tian-Miao Ou, Yong Zhao, Peng Lv, Shi-Ke Wang, Tianpeng Zhang, Jian Ren, and Jia-Heng Tan
- Subjects
0301 basic medicine ,Models, Molecular ,Clinical Biochemistry ,Sequence (biology) ,Biology ,010402 general chemistry ,G-quadruplex ,Ligands ,01 natural sciences ,Biochemistry ,Cell Line ,03 medical and health sciences ,Drug Discovery ,Consensus Sequence ,Consensus sequence ,Humans ,heterocyclic compounds ,Molecular Biology ,Binding selectivity ,Pharmacology ,Base Sequence ,Genome, Human ,Telomere ,Molecular biology ,0104 chemical sciences ,Cell biology ,G-Quadruplexes ,030104 developmental biology ,Nucleic acid ,Molecular Medicine ,Human genome ,Chromatin immunoprecipitation ,HeLa Cells ,Single-Chain Antibodies - Abstract
G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel single-chain variable fragment (scFv) antibody, D1, with high binding selectivity for parallel G-quadruplexes in vitro and in vivo. Genome-wide chromatin immunoprecipitation using D1 and deep-sequencing revealed the consensus sequence for parallel G-quadruplex formation, which is characterized by G-rich sequence with a short loop size (
- Published
- 2016
32. 12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA
- Author
-
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
33. Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands
- Author
-
Ding Li, Jia-Heng Tan, Pei-Fen Yao, Xiao-Xiao Wang, Lian-Quan Gu, Tian-Miao Ou, Zhi-Shu Huang, Wei-Jia Chen, and Chen-Xi Zhou
- Subjects
Circular dichroism ,Molecular model ,Stereochemistry ,Clinical Biochemistry ,Carbazoles ,Down-Regulation ,Pharmaceutical Science ,HL-60 Cells ,Molecular Dynamics Simulation ,Ligands ,G-quadruplex ,Biochemistry ,Proto-Oncogene Proteins c-myc ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Gene expression ,Fluorescence Resonance Energy Transfer ,Humans ,heterocyclic compounds ,Promoter Regions, Genetic ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Chemistry ,Circular Dichroism ,Organic Chemistry ,Hep G2 Cells ,Surface Plasmon Resonance ,G-Quadruplexes ,Cell culture ,Cancer cell ,Molecular Medicine - Abstract
A series of 1,8-dipyrazolcarbazole (DPC) derivatives (6a-6d, 7a-7d) designed as G-quadruplex ligands have been synthesized and characterized. The FRET-melting and SPR results showed that the DPC derivatives could well recognize G-quadruplex with strong discrimination against the duplex DNA. In addition, the DPC derivatives showed much stronger stabilization activities and binding affinities for c-myc G-quadruplex rather than telomeric G-quadruplex. Therefore, their interactions with c-myc G-quadruplex were further explored by means of CD spectroscopy, PCR-stop assay, and molecular modeling. In cellular studies, all compounds showed strong cytotoxicity against cancer cells, while weak cytotoxicity towards normal cells. RT-PCR assay showed that compound 7b could down-regulate c-myc gene expression in Ramos cell line, while had no effect on c-myc expression in CA46 cell line with NHE III(1) element removed, indicating its effective binding with G-quadruplex on c-myc oncogene in vivo.
- Published
- 2012
34. Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation
- Author
-
Yan-Ping Li, Lian-Quan Gu, Shuo-Bin Chen, Wen-Jie Ye, Zhi-Shu Huang, Ding Li, Jia-Heng Tan, Tian-Miao Ou, Jin-Qiang Hou, and Jin-wu Yan
- Subjects
Models, Molecular ,Aché ,Amyloid beta ,Stereochemistry ,Clinical Biochemistry ,Kinetics ,Pharmaceutical Science ,Inhibitory postsynaptic potential ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alkaloids ,Drug Discovery ,Animals ,Horses ,Molecular Biology ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,Isaindigotone ,biology ,Organic Chemistry ,Stereoisomerism ,Acetylcholinesterase ,language.human_language ,chemistry ,Drug Design ,Electrophorus ,Quinazolines ,language ,biology.protein ,Curcumin ,Molecular Medicine ,Cholinesterase Inhibitors ,Selectivity ,Protein Binding - Abstract
A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. The synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced Aβ aggregation inhibitory activity than a reference compound curcumin. The structure–activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced Aβ aggregation was further studied using CD, EM, molecular docking and kinetics.
- Published
- 2012
35. Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3-b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors
- Author
-
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
- Subjects
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
36. Synthesis and Biological Evaluation of Novel Bouchardatine Derivatives as Potential Adipogenesis/Lipogenesis Inhibitors for Antiobesity Treatment
- Author
-
Honggen Wang, Jia-Heng Tan, Shi-Liang Huang, Zhi-Shu Huang, Yong Rao, Hong Liu, Gao Lin, Lian-Quan Gu, Tian-Miao Ou, Ji-Ming Ye, Ding Li, and Hong Yu
- Subjects
Cell cycle checkpoint ,Cell ,Pharmacology ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Indole Alkaloids ,chemistry.chemical_compound ,Mice ,AMP-activated protein kinase ,3T3-L1 Cells ,Drug Discovery ,medicine ,Animals ,Humans ,Triglycerides ,Natural product ,Adipogenesis ,biology ,Cholesterol ,Lipogenesis ,Cell Cycle Checkpoints ,Hep G2 Cells ,medicine.anatomical_structure ,chemistry ,Biochemistry ,biology.protein ,Quinazolines ,Molecular Medicine ,Anti-Obesity Agents ,Signal transduction ,Signal Transduction - Abstract
Our recent study has shown that the natural product bouchardatine (1) can reduce the triglyceride (TG) content in 3T3-L1 adipocytes (EC50 ≈ 25 μM). Here, we synthesized two series of compounds by introducing amine side chains at the 5 or 8 position of 1 and evaluated the lipid-lowering activity of derivatives. It was found that some of the compounds had significant lipid-lowering effects, and the most active compound 3d showed better activity (EC50 = 0.017 μM) than 2 (EC50 = 0.086 μM), a compound reported by us. Further, the mechanism studies revealed that 3d blocked TG accumulation via activation of the LKB1-AMPK signaling pathway, efficiently down-regulating the expression of key regulators of adipogenesis/lipogenesis. Cell uptake assay and confocal imaging of 3d in cells indicated that compound 3d had favorable cell permeability. Our results suggest that 3d may be a promising agent for the treatment of obesity and related metabolic disorders.
- Published
- 2015
37. Synthesis and evaluation of mansonone F derivatives as topoisomerase inhibitors
- Author
-
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
38. 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
39. Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation
- Author
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Shi-Liang Huang, Fang-Xian Ning, Ding Li, Zhi-Shu Huang, Yong-Cheng Li, Min-Hua Nie, Lian-Quan Gu, Jia-Heng Tan, Yan-Ping Li, Tian-Miao Ou, and Meng-Bi Yang
- Subjects
Models, Molecular ,Tertiary amine ,Cell Survival ,Amyloid beta ,Stereochemistry ,Crystallography, X-Ray ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Structure–activity relationship ,Methiodide ,Butyrylcholinesterase ,Pharmacology ,Amyloid beta-Peptides ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Stereoisomerism ,General Medicine ,Acetylcholinesterase ,Peptide Fragments ,Enzyme inhibitor ,biology.protein ,Cholinesterase Inhibitors - Abstract
A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease.
- Published
- 2011
40. Synthesis and biological evaluation of novel N,N′-bis-methylenedioxybenzyl-alkylenediamines as bivalent anti-Alzheimer disease ligands
- Author
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Jia-Heng Tan, Zhi-Shu Huang, Wen Luo, Yan-Ping Li, and Lian-Quan Gu
- Subjects
Curcumin ,Aché ,Stereochemistry ,Diamines ,Ligands ,Fibril ,Bivalent (genetics) ,Benzophenones ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Alzheimer Disease ,Drug Discovery ,Humans ,Enzyme Inhibitors ,IC50 ,Cells, Cultured ,Butyrylcholinesterase ,Cholinesterase ,Pharmacology ,Methylene Chloride ,Amyloid beta-Peptides ,biology ,General Medicine ,Acetylcholinesterase ,language.human_language ,Enzyme Activation ,chemistry ,Biochemistry ,biology.protein ,language - Abstract
A novel series of N,N'-bis-methylenedioxybenzyl-alkylenediamines 5a-5g have been designed, synthesized and evaluated as bivalent anti-Alzheimer's disease ligands. The enzyme inhibition assay results indicated that compounds 5e-5g inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the micromolar range (IC(50), 2.76-4.24 µM for AChE and 3.02-5.14 µM for BuChE), which was in the same potential as the reference compound rivastigmine (IC(50), 5.50 µM for AChE and 1.60 µM for BuChE). It was found that compounds could bind simultaneously to the peripheral and catalytic sites of AChE. β-Amyloid (Aβ) aggregation inhibition assay results showed that compound 5e exhibited highest self-mediated Aβ fibril aggregation inhibition activity (40.3%) with a similar potential as curcumin (41.6%). It was also found that 5e-5g did not affect neuroblastoma cell viability at the concentration of 50 μM.
- Published
- 2011
41. 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
42. Design of Selective G-quadruplex Ligands as Potential Anticancer Agents
- Author
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Jianyong Wu, Jia-Heng Tan, and Lian-Quan Gu
- Subjects
Pharmacology ,Base Sequence ,Low toxicity ,Chemistry ,High selectivity ,Cancer drugs ,Antineoplastic Agents ,DNA ,General Medicine ,Ligands ,G-quadruplex ,Combinatorial chemistry ,Substrate Specificity ,G-Quadruplexes ,DNA metabolism ,Dna genetics ,Drug Design ,Drug Discovery ,Humans ,Substrate specificity ,heterocyclic compounds ,Base sequence ,Amino Acid Sequence - 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.
- Published
- 2008
43. 5-N-Methylated Quindoline Derivatives as Telomeric G-Quadruplex Stabilizing Ligands: Effects of 5-N Positive Charge on Quadruplex Binding Affinity and Cell Proliferation
- Author
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Ning Sun, Jia Heng Tan, Dan Peng, Yu Jing Lu, Lian Quan Gu, Wei Yan Shao, Tian Miao Ou, Jin-Qiang Hou, Wei Bin Wu, Kwok Yin Wong, Xian Zhang Bu, Dik-Lung Ma, Xiaodong Wang, and Zhi Shu Huang
- Subjects
Models, Molecular ,Circular dichroism ,Indoles ,Molecular model ,Guanine ,Stereochemistry ,Ligands ,G-quadruplex ,Methylation ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alkaloids ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,Telomerase ,Cell Proliferation ,Cell-Free System ,Circular Dichroism ,Telomere ,Ligand (biochemistry) ,G-Quadruplexes ,Förster resonance energy transfer ,Cryptolepine ,chemistry ,Potassium ,Quinolines ,Thermodynamics ,Molecular Medicine ,Dialysis - 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.
- Published
- 2008
44. A new application of click chemistry in situ: development of fluorescent probe for specific G-quadruplex topology
- Author
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Tian-Miao Ou, Zhi-Shu Huang, Shuo-Bin Chen, Xiao Chen, Ming-Hao Hu, Meicun Yao, Jia-Heng Tan, and Lian-Quan Gu
- Subjects
In situ ,Multidisciplinary ,Binding Sites ,Drug discovery ,Chemistry ,Aspartate-tRNA Ligase ,RNA, Transfer, Amino Acyl ,G-quadruplex ,Topology ,Fluorescence ,Article ,Protein Structure, Tertiary ,G-Quadruplexes ,Molecular Docking Simulation ,Protein structure ,Spectrometry, Fluorescence ,Nucleic Acids ,Click chemistry ,Side chain ,heterocyclic compounds ,Click Chemistry ,Topology (chemistry) ,Fluorescent Dyes - Abstract
Target-guided synthesis is an approach to drug discovery that allows the target to self-assemble its own binding agents. So far, target-guided synthesis and especially in situ click chemistry have attracted extensive attention and have led to the identification of highly potent inhibitors for proteins. In this study, we expand the application of in situ click chemistry and present a procedure using this approach to identify selective fluorescent probes for a specific topology of G-quadruplex nucleic acids, the parallel G-quadruplexes. On this basis, compound 15 assembled by triarylimidazole scaffold and carboxyl side chain was a positive hit, demonstrating highly potential in the sensitive and selective detection of parallel G-quadruplexes. Such selective fluorescence response can be rationalized in terms of different binding affinities between 15 and G-quadruplexes. Our work accordingly represents a new development towards the application of in situ click chemistry to develop selective fluorescent probes and may also shed light on the search for probes for a specific G-quadruplex topology.
- Published
- 2015
45. Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5' Untranslated Region (UTR) of Its mRNA
- Author
-
Zhi-Shu Huang, Pei-Fen Yao, Jing Lin, Lian-Quan Gu, Ding Li, Tian-Miao Ou, Zhen-Quan Liu, Jie Dai, Xiao-Qin Wang, Shi-Liang Huang, and Jia-Heng Tan
- Subjects
Untranslated region ,Five prime untranslated region ,ADAM10 ,Carbazoles ,ADAM10 Protein ,Structure-Activity Relationship ,Drug Discovery ,Disintegrin ,Protein biosynthesis ,Humans ,RNA, Messenger ,Messenger RNA ,biology ,Chemistry ,Quinolinium Compounds ,RNA ,Membrane Proteins ,Stereoisomerism ,Small molecule ,Molecular biology ,Cell biology ,G-Quadruplexes ,ADAM Proteins ,HEK293 Cells ,Protein Biosynthesis ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,5' Untranslated Regions ,HeLa Cells - Abstract
Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of β-amyloid (Aβ) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aβ40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
- Published
- 2015
46. Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes
- Author
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Jia-Heng Tan, Lian-Quan Gu, Hong Liu, Ji-Ming Ye, Tian-Miao Ou, Gao Lin, Zhi-Shu Huang, Yong Rao, Shi-Liang Huang, and Hong Yu
- Subjects
CCAAT-Enhancer-Binding Protein-delta ,Cell Survival ,Coenzyme A ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Down-Regulation ,AMP-Activated Protein Kinases ,Biochemistry ,Indole Alkaloids ,chemistry.chemical_compound ,Mice ,3T3-L1 Cells ,Drug Discovery ,Adipocytes ,CCAAT-Enhancer-Binding Protein-alpha ,Animals ,RNA, Messenger ,Protein kinase A ,Molecular Biology ,Fatty acid synthesis ,Cell Proliferation ,Adipogenesis ,biology ,CCAAT-Enhancer-Binding Protein-beta ,Lipogenesis ,Organic Chemistry ,Acetyl-CoA carboxylase ,AMPK ,Cell Cycle Checkpoints ,PPAR gamma ,Fatty acid synthase ,chemistry ,biology.protein ,Molecular Medicine ,Anti-Obesity Agents ,Sterol Regulatory Element Binding Protein 1 ,Signal Transduction - Abstract
Bouchardatine (1), a naturally occurring β-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of 1 was investigated in 3T3-L1 adipocytes. Our study showed that 1 could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPβ, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that 1 persistently activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of 1 on adipogenesis and lipogenesis. Our data suggest that 1 can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders.
- Published
- 2015
47. Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors
- Author
-
Jia-Heng Tan, Yan-Wen Mai, Bing-Lei Yao, Ding Li, Pei-Fen Yao, Shuo-Bin Chen, Zhi-Shu Huang, Tian-Miao Ou, Hua-Ting Xie, Shi-Liang Huang, Lian-Quan Gu, and Honggen Wang
- Subjects
Stereochemistry ,HL-60 Cells ,Cleavage (embryo) ,HeLa ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Humans ,Topoisomerase II Inhibitors ,Amines ,Cytotoxicity ,Biological evaluation ,Cell Proliferation ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Topoisomerase ,Organic Chemistry ,General Medicine ,biology.organism_classification ,DNA Topoisomerases, Type II ,Design synthesis ,DNA Topoisomerases, Type I ,Cell culture ,Drug Design ,biology.protein ,Phenazines ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors ,K562 Cells ,Human cancer ,HeLa Cells - Abstract
A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of hTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.
- Published
- 2014
48. DNA G-quadruplex binders: a patent review
- Author
-
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
49. Synthesis and Evaluation of Quinazolone Derivatives as a New Class of c-KIT G-Quadruplex Binding Ligands
- Author
-
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
50. Design, synthesis and biological evaluation of novel mansonone E derivatives prepared via CuAAC click chemistry as topoisomerase II inhibitors
- Author
-
Zhi-Shu Huang, Chun-Yan Li, Tian-Miao Ou, Shi-Tian Zhuo, Shi-Liang Huang, Zhi-Hong Huang, Ding Li, Lian-Quan Gu, Hua-Ting Xie, and Jia-Heng Tan
- Subjects
Stereochemistry ,Triazole ,Antineoplastic Agents ,HL-60 Cells ,Cleavage (embryo) ,HeLa ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Cell Line, Tumor ,Drug Discovery ,Humans ,Topoisomerase II Inhibitors ,Cytotoxicity ,Pharmacology ,Binding Sites ,biology ,Topoisomerase ,Organic Chemistry ,General Medicine ,biology.organism_classification ,Combinatorial chemistry ,Cycloaddition ,Enzyme Activation ,Molecular Docking Simulation ,chemistry ,biology.protein ,Click chemistry ,Click Chemistry ,Topoisomerase-II Inhibitor ,K562 Cells ,Sesquiterpenes ,HeLa Cells ,Naphthoquinones ,Protein Binding - Abstract
Two series of novel C-9 chloro- and bromo-substituted mansonone E derivatives with triazole moieties at the C-3 position were prepared by using copper-catalysed azide–alkyne cycloaddition click chemistry. These compounds were found as potent inhibitors of topoisomerase II (Topo II) and topoisomerase I (Topo I). The Topo II-mediated pBR322 DNA relaxation and cleavage assay showed that the derivatives might act as catalytic inhibitors. Their cytotoxic activities against A549, HL-60, K562 and HeLa cells were evaluated, indicating that these compounds were potent antitumour agents. Their structure activity relationships and molecular docking study revealed that the substituents of the triazole were particularly important for cytotoxicity.
- Published
- 2013
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