- LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors
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Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.
- Li, Guo-Bo,Ji, Sen,Yang, Ling-Ling,Zhang, Rong-Jie,Chen, Kai,Zhong, Lei,Ma, Shuang,Yang, Sheng-Yong
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Read Online
- Synthesis and biological evaluation of novel 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives as potential antitumor agents
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A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.
- Hu, Min,Meng, Nana,Xia, Yong,Xu, Youzhi,Yu, Luoting,Zeng, Xiuxiu,Zhou, Shuyan
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- Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
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A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
- Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
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p. 15651 - 15670
(2021/11/16)
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- Sorafenib sulfydryl derivative and application thereof
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The invention belongs to the field of medicine, and relates to a sorafenib sulfhydryl derivative and application thereof, in particular to a sorafenib sulfhydryl derivative and application thereof in preparation of an anti-tumor drug targeted delivery carrier. The structure of the sorafenib sulfhydryl derivative is shown as the following formula, a sulfhydryl functional group is introduced into pyridine-2-formamide of an anti-tumor small-molecule targeted drug sorafenib, and sorafenib can be coupled to free amino of polypeptide through proper linker molecules by utilizing the sulfhydryl functional group, so that a sorafenib polypeptide conjugate is constructed, the conjugate can give play to the targeting effect and tumor inhibition effect of sorafenib at the same time, and can be used as a targeting delivery carrier of antitumor drugs.
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Paragraph 0019-0021
(2021/04/10)
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- Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design
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Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.
- Tan, Ninghua,Wang, Linxiao,Wang, Zhe,Zhang, Qian,Zhu, Wufu
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- 4 -phenoxypyridine compound containing quinoxalinone and application thereof (by machine translation)
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The invention belongs to the field of medicines, and particularly relates to 4 -phenoxypyridine compounds containing quinoxalinone and application thereof. The 4 -phenoxypyridine compound containing quinoxalinone has the structure of the general formula (I). The invention also relates to the application of the compound of the general formula (I) to inhibit c-Met kinase and provide 4 -phenoxypyridine compounds containing quinoxalinone and pharmaceutically acceptable salts thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression c-Met kinase. (by machine translation)
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- Introduction of mercaptoethyl at sorafenib pyridine‐2‐amide motif as a potentially effective chain to further get sorafenib‐PEg‐DGL
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The crystal structure of the sorafenib and B‐RAF complex indicates that the binding cavity occupied by the pyridine‐2‐carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti‐cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine‐2‐amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib‐PEG‐DGL, which could be developed as a delivery vehicle to improve the concentration of anti‐tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.
- Chen, Ying,Kuerbana, Kudelaidi,Wan, Qi,Wang, Ke,Ye, Li,Yu, Zhihui
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- Substituted pyridine-2-formamide compound and application thereof
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The invention belongs to the technical field of medicinal chemistry, and relates to a substituted pyridine-2-formamide compound and application thereof, wherein specifically the substituted pyridine-2-formamide compound has a structure represented by a formula I. According to the invention, based on excellent in vitro inhibition activity on VEGFR-2 kinase and PDGFR-beta kinase and HUVEC cell inhibition activity, the compound can be used as a small-molecular tyrosine kinase (especially Raf kinase) inhibitor, has the effect of inhibiting cell proliferation and angiogenesis, has good antitumor activity, and has a good effect of treating tumor diseases of mammals (including human beings).
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Paragraph 0144; 0150-0154
(2020/07/15)
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- Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities
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Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.
- Zhong, Lili,Hou, Chenhui,Zhang, Liang,Zhao, Jianchun,Li, Feng,Li, Wenbao
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p. 341 - 350
(2018/10/02)
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- Preparation and application of 2-pyridine carboxamide compound
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The invention relates to a 2-pyridine carboxamide derivative as shown in a formula I, and pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof. Substituents R1, R2, X and Y have themeanings given in the description. The invention further relates to a compound in the general formula I, and the compound has the strong inhibition effect on FLT-3; the invention further relates to the applications of the compound, and the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to preparation of drugs for treating diseases caused by abnormal high expression of FLT-3kinase, especially the applications to preparation of drugs for treating and/or preventing cancers.
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- Method for preparing sorafenib tosylate salt targeted anti-tumor drug
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The invention discloses a method for preparing a sorafenib tosylate salt targeted anti-tumor drug. The method is characterized in that a synthesis route is as followings (please see the specificationsfor the synthesis route), wherein carbonate (M2CO3) in the synthesis route is sodium carbonate, potassium carbonate or cesium carbonate, and a solvent in the synthesis route is MDF or DMA. The carbonate is adopted to replace potassium tert-butoxide, reaction operation is greatly simplified, and the cost is lowered; and through repeated testing and condition screening, the problem of excessively long reaction time is solved finally through heating reflux.
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Paragraph 0061; 0063; 0064; 0065; 0072; 0074; 0075; 0080
(2019/06/08)
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- A urea compound of preparation method
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The invention relates to a preparation method of a urea compound, belongs to the technical field of pharmacy and in particular relates to a preparation method of sorafenib. The preparation method comprises the following steps: forming a mixed solution by using 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide solids, a solvent and water; stirring, and then removing a water layer; and reacting with 4-chloro-3-trifluoromethyl-phenyl isocyanate to prepare a target product namely sorafenib. According to the preparation method, a reactant is mixed with water to remove alkali and avoid the generation of impurities, thereby obtaining a high-purity product; and the preparation method is simple to operate and easy to control, and is suitable for industrial production.
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Paragraph 0048-0051; 0056; 0057; 0059-0060
(2019/07/04)
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- KINASE INHIBITOR COMPOUNDS, COMPOSITIONS, AND METHODS OF TREATING CANCER
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The present invention relates to a compound having the structure of formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, where X, Y, Z, R, R1, R2, R3, R4, R5, and R6 are as described herein. The present invention also relates to compositions containing the compound having the structure of formula (I), and a method of treating cancer in a subject.
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- Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents
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A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α PDGFR-β c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.
- Duan, Yongli,Xu, Shan,Xiong, Hehua,Wang, Linxiao,Zhao, Bingbing,Wang, Ping,Wang, Caolin,Peng, Yiqing,Cai, Shifan,Luo, Rong,Zheng, Pengwu,Tang, Qidong
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p. 254 - 259
(2018/01/10)
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- Preparation and application of 2-carbamoyl-4-heteroaromatic pyridine compounds
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The invention provides 2-carbamoyl-4-heteroaromatic pyridine derivatives and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof. The substituent groups R1, R2 and Y have definitions in the specification. The invention further relates to compounds with a general formula I having strong effects of inhibiting c-Met kinase, and also relates to an application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of medicines for treating diseases caused by abnormal high expression of the c-Met kinase, particularly an application in preparation of medicines for treating and/or preventing cancers.
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- Pyridazinone-containing 4-phenoxy-pyridine compound and application thereof
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The invention discloses a pyridazinone-containing 4-phenoxy-pyridine compound with structure as shown in formula (I) and application thereof. The in vitro cell activity experiment verifies that the pyridazinone-containing 4-phenoxy-pyridine compound has good effect on inhibiting human lung carcinoma A549, human gastric carcinoma cell BGC-823, human gastric carcinoma cell MKN-45, human lung carcinoma H460 and human colon cancer cell HT-29. The invention also relates to application of the compound as shown in formula I in high inhibition of VEGFR2 kinase, and also relates to the application of the compound and pharmacologically acceptable salt, an aquo-complex a solvent compound or a prodrug in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression ofVEGFR2 kinase, and particularly application in preparation of drugs for treating and/or preventing cancers. The formula refers to the description.
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- Preparation method of Sorafenib tosylate related intermediate
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The invention discloses a preparation method of a Sorafenib tosylate related intermediate, and belongs to the technical field of medicines. -CONHCH3 is generated by -COOH, halogen atoms are connectedonto a pyridine ring at normal temperature to synthesize a compound 3, and energy consumption is reduced. Moreover, post-treatment is simple, operation is easy, the purity of a treated product at eachstep can reach 95%, the product can be directly used for a next step, and the preparation method is suitable for industrial production.
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- A method for synthesizing intermediate zola non-nepal
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The invention discloses a synthesis method for a sorafenib intermediate. The synthesis method comprises the following steps: using N-methyl(4-chlorine-2pyridyl)formamide and p-nitrophenol as raw materials, and conducting etherification reaction and hydrogenation reduction to obtain 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (a compound 1). The yield of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide obtained according to the synthesis method is 80% or above, the yield of the sorafenib intermediate is 90% or above, and the synthesis process is simple and easy to control, and suitable for large-scale industrialized production.
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Paragraph 0028; 0033; 0036; 0039; 0042; 0045; 0048
(2018/07/30)
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- The preparation method of the zola non-nepal (by machine translation)
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The invention discloses a method for preparing zola non-nepal, the states the zola non-nepal the chemical name is 4 - {4 - [( {4 - chloro - 3 - (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} - N - methylpyridine - 2 - carboxamide; the process of the invention has simple process, raw materials are easy, economic and environmental protection, help to realize industrialization, can promote the zola non-nepal drug of economic and technological development, and reduces the production cost, high yield, low environmental pollution, is suitable for mass production. (by machine translation)
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Paragraph 0012-0014
(2018/04/28)
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- A preparation method of zola non-nepal (by machine translation)
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The invention relates to a preparation method of zola non-nepal, the method comprises the following steps: the aminophenol heating molten, in KOH under the action of the 4 - chloro - N - methyl pyridine - 2 - carboxamide [...] condensation reaction to produce intermediate I; I after the intermediate, 3 - trifluoromethyl - 4 - chlorobenzene with methanol in the catalyst under the action of the "one-pot" reaction, after treatment [...], further purify zola non-nepal pure product. The method of the invention high conversion rate, without endangering the safe, pollution-free, mild reaction conditions, high yield, high purity of the product and is suitable for industrial production. (by machine translation)
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Paragraph 0034; 0035
(2019/01/08)
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- Preparation method of sorafenib
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The invention relates to a preparation method of sorafenib. The method comprises the following steps of allowing p-nitrophenol and 4-chlorine-N-picoline-2-formamide to react under the action of anhydrous potassium carbonate and PEG (polyethylene glycol)-400, generating a compound I via hydrazine hydrate reduction, allowing the compound I, 3-trifluoromethyl-4-chloroaniline and diphenyl carbonate orN,N-disuccinimidyl carbonate to give a 'one-pot' reaction by the action of a catalyst, performing post-treatment to form a sorafenib crude product, and performing further purification to form pure sorafenib. The method is high in conversion rate, safe, free from harm and pollution, mild in reaction condition, high in yield and applicable to industrial production, and can ensure high product purity.
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Paragraph 0034-0049
(2018/07/30)
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- A preparation method of zola non-nepal (by machine translation)
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The invention relates to a preparation method of zola non-nepal, the method comprises the following steps: the P-nitrophenol heating molten, in KOH under the action of the 4 - chloro - N - methyl pyridine - 2 - carboxamide [...] condensation reaction, by hydrazine hydrate also primary into intermediate I; I after the intermediate, 3 - trifluoromethyl - 4 - chloroaniline in under the action of a catalyst carried out with methyl ethyl carbonate one-pot reaction, after treatment [...], further purify zola non-nepal pure product. The method of the invention high conversion rate, without endangering the safe, pollution-free, mild reaction conditions, high yield, high purity of the product and is suitable for industrial production. (by machine translation)
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Paragraph 0028; 0034-0047
(2018/07/30)
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- N,N'-bis-substituted aryl thiourea derivatives and synthetic method and application thereof
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The invention discloses N,N'-bis-substituted aryl thiourea derivatives which are a series of compounds simultaneously containing various substituted aromatic ring structures and asymmetric substituted thiourea structures and are all novel structural compounds which are not reported in the literature. The biological activity test analysis of all the target compounds includes determination of DPPH antioxidant activity and antiviral activity. Results indicate that, in general, the designed and synthesized compounds are novel in structures and have the antioxidant activity and the antiviral activity revealed for the first time. In addition, the unknown biological activity is not fully elucidated, and thus the compounds are expected to provide a certain material basis for further research and development of new drugs.
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- The sulfonylurea-containing structure of the preparation and application of zola non-nepal derivatives (by machine translation)
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The invention discloses a sulfonylurea structure containing sorafenib derivative, its geometric isomer and pharmaceutically acceptable salt, hydrate, solvate or prodrug, and application thereof in preparation of drugs treating and/or preventing hyperplastic diseases, application in preparation of drugs treating and/or preventing cancers, and application in preparation of drugs treating and/or preventing lung cancer, liver cancer, gastric cancer, colon cancer and breast cancer.
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- LIVER-TARGETED PRODRUG COMPOSITIONS AND METHODS OF USING THE SAME
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Disclosed are compositions and methods of delivering a drug to a liver cell or liver tissue in a subject. In some forms, the composition is a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together. The hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
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- A process for the preparation and purification of 4 - (4 - aminophenoxy) - N - methylpyridine - 2 - carboxamide
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The invention discloses a method for preparing and purifying sorafenib key intermediate 4-(4-amino-phenoxy)-N-methylpyridine-2-formamide.
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Paragraph 0038-0041; 0042-0043
(2017/12/04)
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- 4-substituted pyridine-2-formamide compound, preparation method thereof and application
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The invention discloses a 4-substituted pyridine-2-formamide compound, a preparation method thereof and an application. The 4-substituted pyridine-2-formamide compound has a structure as shown in a formula I, and the chemical name of the compound is 4-{4-[3-(4-chlorine-3-trifluoromethyl-phenyl)-ureide]-3-carboxyl phenoxy}-N-picoline-2-carboxylic methylamine. According to the preparation method of the 4-substituted pyridine-2-formamide compound, 4-chlorine-2-picolinic acid serves as an initial raw material, and the compound in the formula I is prepared by acylating chlorination, amination, substitution reaction and condensation reaction. The 4-substituted pyridine-2-formamide compound retains a Sorafenib efficacy structure, 5-aminosalicylic acid or aminosalicylic acid ester achieving a positive pharmacological function in the metabolic process replaces p-aminophenol with large toxic and side effects, efficacy can be improved, and the toxic and side effects are reduced.
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Paragraph 0086; 0087; 0089
(2018/03/28)
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- ARYL UREAS WITH ANGIOGENISIS INHIBITING ACTIVITY
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This invention relates to methods of using aryl ureas to treat diseases mediated by the VEGF induced signal transduction pathway characterized by abnormal angiogenesis or hyperpermeability processes.
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- A process for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid (by machine translation)
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The invention discloses a method for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid. The method is as follows: P-amino-phenol and 4?Polybromide?2?Cyano pyridine the reaction is performed in the presence of sodium hydroxide, then is acidified to obtain 4?(4?Aminophenoxy)?2?(Formic acid) pyridine; the substitution after the reaction, thionyl chloride, in the presence of potassium carbonate, the reaction is carried out with methyl amine, to obtain the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine; then with compound 4?Chlorotrifluoromethylbenzene?3?Phenylisocyanate (trifluoromethyl) after direct condensation, with toluene-P-sulfonic acid salifying-toluene-sulfonic acid SUO draw non-Buddhist nun. The preparation method adopts a 4?Polybromide?2?Cyano pyridine as the starting raw materials for preparing the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine, the follow-up at the same time simplifying the step of reacting, simple steps of the reaction, the yield of the product is high. (by machine translation)
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Paragraph 0037
(2016/10/17)
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- Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug
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The invention provides a deuterated bisarylurea compound and a preparation method thereof, and application of the compound in preparation of an antitumor drug. The compound has a structure as shown in a general formula (I). The preparation method comprises the following steps: with methyl 4-chloropyridine-2-formate as a raw material, sucjecting methyl 4-chloropyridine-2-formate and methylamine or deuterated methylamine to a substitution reaction; then subjecting a product obtained in the previous step to condensation with p-aminophenol or deuterated p-aminophenol; and reacting a product obtained in the previous step with 4-chloro-3-(trifluoromethyl)phenyl isocyanate or deuterated 4-chloro-3-(trifluoromethyl)phenyl isocyanate so as to prepare the deuterated bisarylurea compound. Experiment results show that the deuterated bisarylurea compound provided by the invention has tumor treatment effect. The invention also provides application of the compound to research and development of the antitumor drug.
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- N-indazole substituted thiourea derivatives and preparation method and application thereof
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The invention discloses N-indazole substituted thiourea derivatives and a preparation method and application thereof and belongs to the technical field of chemical medicine.The thiourea derivatives are a series of compounds simultaneously containing the 1H-indazole ring structure and the asymmetrical thiourea structure, and the compounds are not reported in the literature.The bioactivity test result analysis of the thiourea derivatives show that the compounds are good in antioxidant activity, the average scavenging rate is above 80%, the scavenging rate of the compound 12b, the compound 12c, and the compound 12d and the compound 12h is higher than 90%, the scavenging activity IC50 of the compound 12h on DPPH is 0.14mg/mL; part of the target compounds has certain inhibition activity on herpes viruses, vaccinia viruses, reoviruses, Coxsackie viruses, Feline coronary herpes viruses, HIV viruses and the like, and the compound 12c and the compound 12n are high in antivirus activity; the synthesized compounds hopefully have new bioactivity which is not expounded, and a certain material basis is provided for the development of new medicine.
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- Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives
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Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.
- Wang, Wenhui,Wu, Chunjiang,Wang, Jianqiang,Luo, Rong,Wang, Caolin,Liu, Xiaobo,Li, Jiqing,Zhu, Wufu,Zheng, Pengwu
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p. 6166 - 6173
(2016/12/06)
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- 2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
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The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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- Sorafenib compound
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The invention relates to a sorafenib compound and a preparation method of an intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide of the sorafenib compound, and belongs to the technical field of medicine preparation. The preparation method comprises the steps that 4-chloro-N-methyl pyridine-2-formamide and p-aminophhenol are dissolved into polar organic solvent, a phase transfer catalyst and a solid inorganic base carrier are added, after a heating reflux reaction is complete, hot filtration is performed by adding a filter aid, and a crude product is recrystallized through ethyl acetate and methylbenzene or isopropanol to obtain a pure product. The problems that in the prior art, when 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide is prepared, operation is inconvenient, the general reaction time is too long, the yield and the purity are low, and the cost is high are solved. Accordingly, operation is easy, convenient and safe, the reaction time is short, the pure product with the higher purity and yield can be prepared under the normal temperature condition, the difficulty of final product purification is reduced, and the quality stability and medication safety of the sorafenib are further guaranteed.
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Paragraph 0059-0063
(2017/04/06)
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- SORAFENIB ANALOGS AND USES THEREOF
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The present invention provides, inter alia, compounds according to formula I. Also provided are pharmaceutical compositions and kits containing such compounds. Methods for using such compounds, compositions, and kits for treating a subject having system xc-, dysregulation for activating ferroptosis, for inhibiting system xc- in a cell, and for monitoring treatment of a subject having system xc- dysregulation are provided as well.
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Paragraph 0133; 0137; 0138; 0139
(2015/04/22)
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- Synthesis and anti-proliferative activity evaluation of sorafenib derivatives with a 3-arylacryloyl hydrazide unit
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A series of sorafenib derivatives with a 3-arylacryloyl hydrazide unit were designed and synthesized, and their anti-proliferative activity against human cancer cell lines (ACHN, HCT116, MDA-MB-231) were evaluated by MTT assay. Most of the synthesized compounds showed superior or similar cytotoxicity against the selected cell lines to the control sorafenib. Among these derivatives, compounds 8a, 8h, 8l, 8m, 11a and 11b showed potent anti-proliferative activity. Compounds 8h and 8m were selected for further evaluation of biological activity against more cancer cell lines. And oral administration of sorafenib analogue 8h at the same dose of sorafenib (30 mg/kg) in the pancreatic cancer Capan2 and Mia-PaCa2 xenograft models in nude mice showed tumour growth inhibition of 60.98 and 54.59 %, respectively, which is similar to the positive control sorafenib.
- Zhang, Lijing,Li, Yan,Wang, Ke,Qin, Aifang,Chen, Xiaoguang,Feng, Zhiqiang
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p. 1733 - 1743
(2015/04/27)
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- Design, synthesis, activity and docking study of sorafenib analogs bearing sulfonylurea unit
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Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by 1H-NMR, 13C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 cancer cell lines. Some of the compounds showed moderate cytotoxic activity, especially compounds 1-(2,4-difluorophenylsulfonyl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6c) and 1-(4-bromophenylsulfonyl)-3-(4- (2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6f) with the IC50 values against four cancer cell lines ranging from 16.54 ± 1.22 to 63.92 ± 1.81 ?M, respectively. Inhibitory rates against vascular endothelial growth factor receptor-2 (VEGFR2/KDR) kinase at 10 ?M of target compounds were further carried out in this paper in order to investigate the target of these compounds. Structure-activity relationships (SARs) and docking studies indicated that the sulfonylurea unit was important to these kinds of compounds. None of the substitutions in the phenoxy group and small halogen atoms such as 2,4-difluoro substitution of the aryl group contributed to the activity. The results suggested that sulfonylurea sorafenib analogs are worthy of further study.
- Wu, Chunjiang,Wang, Min,Tang, Qidong,Luo, Rong,Chen, Le,Zheng, Pengwu,Zhu, Wufu
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p. 19361 - 19371
(2015/11/27)
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- Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors
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To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition.
- Hwang, Sung Hee,Wecksler, Aaron T.,Zhang, Guodong,Morisseau, Christophe,Nguyen, Long V.,Fu, Samuel H.,Hammock, Bruce D.
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supporting information
p. 3732 - 3737
(2013/07/27)
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- ANTICANCER COMPOUNDS AND PREPARATION METHODS THEREOF
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Two new compounds with anticancer effects of N-[4-chloro-3-(trifluoromethyl)phenyl]-[4-(N-methyl-formamide)(4-pyridyloxy)phenyl]-thiourea and N-[4-chloro-3-(trifluoromethyl)phenyl]-[4-(N-methyl-formamide)(4-pyridylthio)phenyl]-thiourea, and salts thereof are disclosed. Preparation methods of the two new compounds and pharmaceutical compositions containing the new compounds are further disclosed. Experimental studies show that the two new compounds can effectively inhibit the activity of Raf and VEGFR protein kinase, widely inhibit growth of various types of human tumor cell lines and further induce apoptosis of tumor cells. Human tumor heterograft model investigation proves that the two new compounds are effective antineoplastic agents, and can sharply inhibit growth of human liver cancer cells, lung cancer cells and intestinal cancer cells in vivo. Furthermore, the anticancer effects of the compounds are much better than that of Sorafenib.
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- SORAFENIB DERIVATIVES AS sEH INHIBITORS
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The present invention provides compounds for the inhibition of soluble epoxide hydrolase and associated disease conditions.
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Page/Page column 57
(2012/09/10)
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- Design, synthesis and biological activities of thiourea containing sorafenib analogs as antitumor agents
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A novel series of diaryl thiourea containing sorafenib derivatives 9a-t was designed and synthesized. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR and HRMS. Their antiproliferative activities against HCT116 and MDA-MB-231 cell lines, and their inhibitory activities against the phosphorylation of VEGFR were evaluated and described. Some of the compounds showed significant activities against both cell lines and VEGFR. Compounds 9g, 9m, 9o and 9p demonstrated competitive antiproliferative activities to sorafenib, the reference standard, while compounds 9d, 9m, and 9p showed significant inhibitory activities against the phosphorylation of VEGFR.
- Yao, Jianwen,Chen, Jing,He, Zuopeng,Sun, Wei,Xu, Wenfang
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p. 2923 - 2929
(2012/07/14)
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- Design and synthesis of 2-iminothiazolidin-4-one moiety-containing compounds as potent antiproliferative agents
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A new series of 2,5-diaryliminothiazolidin-4-ones were designed and synthesized as potent antiproliferative agents. The antiproliferative activities of the 25 target compounds were evaluated against three cancer cell lines (A549, H460 and HT29) by MTT assay. Pharmacological data indicated that most of the compounds possessed moderate activity, some showed remarkable activity against one or more cell lines. As the most promising compound, 8s (with IC 50 values of 1.1, 0.01 and 1.3μM against the A549, H460 and HT29 cell lines) was 1.1- to 270-fold more potent than the reference drug sorafenib. Furthermore, preliminary structure-activity relationships (SARs) were summarized to provide guidance for further design and discovery of 2-iminothiazolidin-4- one-based antiproliferative agents. A new series of 2,5-diaryliminothiazolidin- 4-ones were designed and synthesized as potent antiproliferative agents. The antiproliferative activities of the 25 target compounds were evaluated against three cancer cell lines (A549, H460 and HT29) by MTT assay. The most promising compound, 8s, was 1.1-270-fold more potent than the reference drug sorafenib. Preliminary structure-activity relationship data provide guidance for further design and discovery of 2-iminothiazolidin-4-one-based antiproliferative agents. Copyright
- Zhai, Xin,Li, Wei,Chen, Dong,Lai, Ruiwei,Liu, Jun,Gong, Ping
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p. 360 - 367
(2012/07/17)
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- Synthesis of aryl urea derivatives from aryl amines and aryl isocyanates
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The present study describes the synthesis of novel diaryl urea derivatives derived from aryl amine and aryl isocyanates. The synthesized compounds are analogs of sorafenib [4-[4-[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]phenoxy]-N-methylpyridine-2- carboxamide] having potential antiproliferative activity.
- Usharani,Bhujanga Rao,Reddy,Dubey
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p. 1802 - 1806
(2011/12/22)
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- Synthesis and cytotoxic evaluation of novel N-methyl-4-phenoxypicolinamide derivatives
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A series of N-methyl-4-phenoxypicolinamide derivatives were synthesized and evaluated in vitro for their cytotoxic activity against A549, H460 and HT29 cell lines. Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity, superior to that of the reference drug sorafenib. As the most promising compound, 8e exhibited potent cytotoxicity with the IC50 value of 3.6, 1.7 and 3.0 μM against A549, H460 and HT-29 cell lines, respectively.
- Li, Wei,Zhai, Xin,Ding, Lu,Sun, Limin,Chen, Xiaomei,Gong, Ping,Sun, Tiemin
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p. 5130 - 5141
(2011/08/06)
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- Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents
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A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity superior to the reference drug sorafenib, especially the most promising compound 7r (with the IC50 value of 0.8, 1.3 and 2.8 μM against A549, H460 and HT29 cell lines, respectively). The activity was found to strongly depend on the substitution pattern of the rhodanine motif at C-5″ position. Results suggested that this series of compounds could serve as the bases for the development of novel antitumor agents. Copyright
- Li, Wei,Zhai, Xin,Zhong, Zheng,Li, Guangyue,Pu, Yongxiao,Gong, Ping
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p. 349 - 357
(2012/01/07)
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- Sorafenib: Radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice
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Sorafenib (Nexavar, BAY43-9006, 1) is a second-generation, orally active multikinase inhibitor that is approved for the treatment of some cancers in patients. In this Letter, we developed [11C]1 as a novel positron emission tomography (PET) probe, and evaluated the influence of ABC transporters-mediated efflux on brain uptake using PET with [11C]1 in P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) knockout mice versus wild-type mice. [11C]1 was synthesized by the reaction of hydrochloride of aniline 2 with [11C]phosgene ([11C] COCl2) to give isocyanate [11C]6, followed by reaction with another aniline 3. Small-animal PET study with [11C]1 indicated that the radioactivity level (AUC0-60 min, SUV × min) in the brains of P-gp/Bcrp knockout mice was about three times higher than in wild-type mice.
- Asakawa, Chiharu,Ogawa, Masanao,Kumata, Katsushi,Fujinaga, Masayuki,Kato, Koichi,Yamasaki, Tomoteru,Yui, Joji,Kawamura, Kazunori,Hatori, Akiko,Fukumura, Toshimitsu,Zhang, Ming-Rong
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scheme or table
p. 2220 - 2223
(2011/06/17)
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- Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf
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STAT3 is a transcription factor that modulates survival-directed transcription. It is persistently activated in many human cancers. Literature has shown that sorafenib, Raf kinase inhibitor, reduces Phospho-STAT3 and induces cell death. A series of sorafenib derivatives were synthesized as new inhibitors for STAT3. Urea, sulfonamide, and carboxamide linkers brought out different SARs from the end of sorafenib. Urea and carboxamide linked derivatives showed greater inhibition against STAT3 activity than sulfonamide linked derivatives. In particular, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4- (4-cyanophenoxy)phenyl)urea (1), a urea linker, was as potent as sorafenib in reducing P-STAT3 level and cell death but no inhibition for Raf activity. Such result provides a new lead for the design of STAT3 inhibitors.
- Chen, Kuen-Feng,Tai, Wei-Tien,Huang, Jui-Wen,Hsu, Cheng-Yi,Chen, Wei-Lin,Cheng, Ann-Lii,Chen, Pei-Jer,Shiau, Chung-Wai
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scheme or table
p. 2845 - 2851
(2011/07/08)
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- PROTEIN KINASE INHIBITORS USEFUL FOR TREATMENT OF CANCERS
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This invention relates to protein kinase inhibitors useful for treating cancers. The present protein kinase inhibitors are those having the structures of the following formula or pharmaceutically acceptable salts thereof. The present compounds can be used to treat protein kinase related diseases such as cancers.
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Page/Page column 5
(2010/12/29)
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- AURORA KINASE MODULATORS AND METHODS OF USE
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The present invention relates to chemical compounds having a general formula I (I) wherein A1-6, L1, R1, R4-6 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinase proteins. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds and methods of treating disease states related to the activity of Aurora kinase.
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Page/Page column 39-40
(2010/04/03)
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- RAF KINASE INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to Raf kinase inhibitors containing zinc-binding and their use in the treatment of Raf related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 22; 25
(2008/12/08)
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