20716-41-0Relevant academic research and scientific papers
Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR
Han, Liqiao,Huang, Xianzhang,Jin, Xing,Li, Xingshu,Liang, Baoxia,Ouyang, Feng,Xu, Yuzhu,Yan, Jun,Zhan, Min,Zhang, Qiaoxuan
, (2021/10/14)
Microtubule target agents (MTAs) are widely-used clinical anti-cancer drugs for decades, but the acquired drug resistance severely restricted their application. Thioredoxin reductases (TrxR) was reported to be overexpressed in most tumors and closely related to high risk of cancer recurrence and drug resistance, making it a potential target for anticancer drug discovery. Multi-target-directed ligands (MTDLs) by a single molecule provide a logical and alternative approach to drug combinations. In this work, based on the structure-activity relationships obtained in our previous study, some structure modifications were performed. On one hand, the retained skeleton structure of MTAs endowed its tubulin polymerization inhibition activity, on the other hand, the selenium-containing structure and α,β-unsaturated ketone moiety endowed the TrxR inhibition activity. As results, the newly obtained compounds exhibited superior anti-proliferative activities towards various human cancer cells and drug-resistance cells, and displayed high selectivity towards various human normal cells. The mechanism study revealed that the dual effect of cell cycle arrest triggered by targeting tubulin and the abnormal accumulation of ROS caused by TrxR inhibition eventually lead to cell apoptosis. Notably, compared with the MTA agents CA-4P, and the TrxR inhibitor Ethaselen, the optimized compound 14c, which served as dual-targeting inhibitor of tubulin and TrxR, exerted greatly improved in vivo anti-tumor activity. In summary, 14c deserved further consideration for cancer therapy.
7-(3,4-dimethoxy-5-selenomethylphenyl)-pyrrolo[2,3-d]pyrimidine and application thereof
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Paragraph 0044-0047, (2021/06/13)
The invention discloses 7-(3,4-dimethoxy-5-selenomethylphenyl)-pyrrolo[2,3-d]pyrimidine and an application thereof The chemical structure of the 7-(3,4-dimethoxy-5-selenomethylphenyl)-pyrrolo[2,3-d]pyrimidine is shown as a formula (a); in the formula (a),
Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities
Ren, Yichang,Wang, Yuxi,Li, Gang,Zhang, Zherong,Ma, Lingling,Cheng, Binbin,Chen, Jianjun
, p. 4498 - 4515 (2021/05/04)
Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound 12b exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC50 value of 50 nM, slightly better than colchicine. 12b exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC50 = 9.7 nM) and the corresponding parental cell line (A2780S, IC50 = 6.2 nM), thus effectively overcoming paclitaxel resistance in vitro. The crystal structure of 12b in complex with tubulin was solved to 2.45 ? resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, 12b displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that 12b is a promising lead compound deserving further investigation as a potential anticancer agent.
Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase
Hitge, Rialette,Petzer, Jacobus P.,Smit, Sharissa,Petzer, Anél
supporting information, (2020/04/17)
Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol–O-methyltransferase (COMT). Based on this, nitrocatechol der
Derivative of Kutkin dimer analog JJA-D0 or its pharmaceutically acceptable salt, preparation method and use thereof
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Paragraph 0085-0086, (2019/01/08)
The invention relates to a derivative of Kutkin dimer analog JJA-D0 or its pharmaceutically acceptable salt, a preparation method and use thereof. The compound has a structure shown as a general formula (I). According to the invention, an alkyl group, an aryl group, a heteroaryl group, an alkoxycarbonylalkyl group, an acyl group, a sulfonate group, an antioxidant group such as a lipoic acid group,a H2S donor group such as a cysteine group, and a NO donor group such as a nitrate group are introduced to JJA-D0, and a series of structurally novel compounds can be synthesized and disclosed. The compounds inhibit NADPH oxidase and have superior anti-oxidation and anti-inflammatory pharmacological mechanisms by comparing with Kutkin, the compounds also have donor groups that provide NO and H2S,can further enhance pharmacological activity, and can be a new class of multifunctional compounds. The disclosed JJA-D0 derivative can be used for preparing health products or drugs for prevention ortreatment of diseases associated with NADPH oxidase, diseases associated with free radicals, diseases associated with inflammation, diseases associated with NO, and diseases associated with H2S.
Synthesis and evaluation of selenium-containing indole chalcone and diarylketone derivatives as tubulin polymerization inhibition agents
Zhang, Shun,An, Baijiao,Li, Jiayan,Hu, Jinhui,Huang, Ling,Li, Xingshu,Chan, Albert S. C.
supporting information, p. 7404 - 7410 (2017/09/25)
Sixteen new selenium-containing indole chalcone and diarylketone derivatives were synthesized and evaluated as tubulin polymerization inhibitors. Among them, compound 25b exhibited the most potent antiproliferative activities against six human cancer cell lines with IC50 values of 0.004-0.022 μM. A microtubule dynamics assay and an immunofluorescence assay confirmed that 25b could effectively inhibit tubulin polymerization (IC50 = 2.1 ± 0.27 μM). Further cellular mechanism studies revealed that 25b induced G2/M phase arrest, which was further evidenced by the decrease in the mitochondrial membrane potential (MMP).
N-SUBSTITUTED 3,4-BIS (CATECHOL) PYRROLE COMPOUNDS, AND THE PREPARATION AND USE THEREOF IN THE TREATMENT OF CANCER
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Paragraph 0041; 0042; 0043, (2015/12/26)
The present invention relates to a compound of formula (I) in which: —m is an integer from 0 to 3, preferably from 0 to 2; n is an integer from 0 to 3, preferably from 0 to 2; m+n≧1; EAG is an electro-attractive group chosen independently from among a halogen atom, an NO2, CF3, CCI3, CN, CO2H, (C═O)NR2, CH═NR, (C═S)OR, (C═O)SR, CS2R, SO2R, SO2NR2, SO3R, P(O)(OR)2, P(O)(R)2, B(OR)2 group where R is a (C1-C6) alkyl radical, a phenyl group or a hydrogen atom; A is a saturated or unsaturated, linear or branched hydrocarbon chain including 1 to 10 atoms of carbon; and R1 and R2 each represent independently from one another a hydrogen atom, a CO-(Ci-C6)-alkyl, (C1-C6) alkyl, phenyl or phenyl-(C1-C6)-alkyl group, in which R1 and R2 form, together with the nitrogen atom they carry, a 5- to 15-member heterocycle, optionally substituted by a (C1-C6) alkyl group; including its stereoisomers and the mixtures thereof, or a pharmaceutically acceptable salt of same.
A concise formation of N-substituted 3,4-diarylpyrroles-synthesis and cytotoxic activity
Egorov, Maxim,Delpech, Bernard,Aubert, Genevieve,Cresteil, Thierry,Garcia-Alvarez, Maria Concepcion,Collin, Pascal,Marazano, Christian
supporting information, p. 1518 - 1524 (2014/03/21)
A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.
Pharmacophore combination as a useful strategy to discover new antitubercular agents
Rana, Dharmarajsinh N.,Chhabria, Mahesh T.,Shah, Nisha K.,Brahmkshatriya, Pathik S.
, p. 370 - 381 (2014/03/21)
The present study is aimed at combining two well-known pharmacophores (pyrazoline and benzoxazole nucleus) to design and synthesize a series of substituted pyrazoline-based benzoxazole derivatives. In vitro antitubercular evaluation against Mycobacterium tuberculosis H37Rv, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains showed that most of the target compounds displayed potent activity (MIC ~1.25-25 μg/mL) where few compounds were found to be better than isoniazid against MDR-TB (MIC = 3.25 μg/mL) and XDR-TB (MIC = 12.5 μg/mL). Cytotoxicity assay of these active compounds in VERO cell lines displayed good selectivity index. In order to gain insights into the plausible binding motifs, the target compounds were docked into enoyl-acyl carrier protein reductase, a molecular target of isoniazid. All the docked compounds occupied the same hydrophobic binding pocket and interacted mostly by dispersion interactions. Contribution of the three pharmacophoric fragments (pyrazoline, benzoxazole and aryl ring) toward protein-ligand binding was evaluated at semi empirical quantum mechanics level. The interaction energies suggested that most of the binding was governed by the benzoxaxole moiety followed by pyrazoline and aryl rings.
Synthesis and biological evaluations of novel apocynin analogues
Lu, Xiaoyu,Wan, Sainan,Jiang, Jie,Jiang, Xiaojian,Yang, Wenjing,Yu, Pei,Xu, Lipeng,Zhang, Zaijun,Zhang, Gaoxiao,Shan, Luchen,Wang, Yuqiang
experimental part, p. 2691 - 2698 (2011/06/27)
We have designed and synthesized a series of novel apocynin analogues, and evaluated their biological activity. Compound 10, an apocynin dimer analogue, compound 12, the lipoic acid (LA) and apocynin conjugate, were the most potent in protecting cells from lipopolysaccharide (LPS)-induced cytotoxicity, had significant activity scavenging ROS induced by LPS, and greatly decreased LPS-induced P67phox protein expression. SAR analysis suggests that modification of apocynin can increase its activity. Our results demonstrate that arming apocynin with a powerful antioxidant such as lipoic acid is a valid strategy to design new apocynin analogues with enhanced biological activity.
