- Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer
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Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.
- Akwii, Racheal,Alvina, Karina,Ashraf-Uz-Zaman, Md,Farshbaf, Mohammad Jodeiri,German, Nadezhda A.,Kallem, Raja Reddy,Mikelis, Constantinos M.,Putnam, William,Sajib, Md Sanaullah,Shahi, Sadisna,Trippier, Paul C.,Wang, Wei,Zhang, Ruiwen
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- Synthesis and biological evaluation of novel 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives as potential antitumor agents
-
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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- Design, synthesis and anticancer activity of a new series of n-aryl-n′-[4-(Pyridin-2-ylmethoxy)benzyl]urea derivatives
-
The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N’-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC50 for MCF7 and PC3 cell lines were even less than 3μM.
- Hou, Shicheng,Liang, Shishao,Zhang, Chao,Han, Yingmei,Liang, Jianhui,Hu, Hongyu,Zhang, Xingeng,Hu, Chun,Liu, Xiaoping,Zhang, Hong
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- Urea compound with gibberellin function inhibition activity as well as preparation method and application thereof
-
The invention belongs to the technical field of plant growth regulators, and particularly discloses a urea compound and a preparation method and application thereof. The structure of the urea compoundis shown as a formula I in the specification. The preparation method of the urea compound provided by the invention has the advantages of cheap raw materials, simple process, mild reaction conditionsand high yield. Related activity studies find that the compound shown in the formula I has good regulation activity on plant growth, can effectively reduce the plant height and promote generation ofside roots, can be used for weed control at high concentration, and is a potential plant growth regulator.
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Paragraph 0048-0051
(2020/05/14)
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- Synthesis and biological evaluation of a new series of 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives as new anticancer agents
-
The diaryl ureas are very important fragments in medicinal chemistry. By means of computer-aided design, 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives were designed and synthesized, and evaluated for their antiproliferative activity against A549, HCT-116, PC-3 cancer cell lines, and HL7702 human normal liver cell lines in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Most of the target compounds demonstrate significant antiproliferative effects on all the selective cancer cell lines. The calculated IC50 values were reported. The target compound 1-(4-chlorophenyl)-3-{4-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methoxy}phenyl}urea (7u) demonstrated the most potent inhibitory activity (IC50 = 2.39 ± 0.10 μM for A549 and IC50 = 3.90 ± 0.33 μM for HCT-116), comparable to the positive-control sorafenib (IC50 = 2.12 ± 0.18 μM for A549 and IC50 = 2.25 ± 0.71 μM for HCT-116). Conclusively, 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives as the new anticancer agents were discovered, and could be used as the potential BRAF inhibitors for further research.
- Feng, Jian,Li, Tai,Liang, Shishao,Zhang, Chuanming,Tan, Xiaoyu,Ding, Ning,Wang, Xin,Liu, Xiaoping,Hu, Chun
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p. 1413 - 1423
(2020/05/22)
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- Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression
-
Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC50 = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
- Lakkaniga, Naga Rajiv,Zhang, Lingtian,Belachew, Binyam,Gunaganti, Naresh,Frett, Brendan,Li, Hong-yu
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- Design, synthesis and antitumor assessment of phenylureas bearing 5-fluoroindolin-2-one moiety
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Background: The development of novel antineoplastic agents remains highly desirable. Objective: This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Methods: Three sets of phenylureas were designed and synthesized and their antiproliferative abil-ity was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). Results: A total of twenty-one new compounds were synthesized and characterized by means of1 H and13 C NMR as well as HR-MS. Three sets of compounds (1a?1c, 2a?2c, and 3a?3c) were ini-tially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a?1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d?1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cyto-toxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF-7) xenograft models without affecting the body weight of its recipients. Conclusion: In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structure-activity studies showed that 1g was the most bioactive antitumor agent among all tested com-pounds, hence a potentially promising lead compound once given further optimization.
- Cai, Yunrui,Chen, Tong,Zhu, Huajian,Zou, Hongbin
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p. 958 - 968
(2020/08/19)
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- Thiazolinone heterocyclic compound, preparation method, medicinal composition and application thereof
-
The invention provides a thiazolinone heterocyclic compound, a preparation method, a medicinal composition and an application thereof. The invention provides an application of the thiazolinone heterocyclic compound in preparation of an NLRP3 inflammasome inhibitor. The thiazolinone heterocyclic compound has a structure as a formula I or an isomer, a prodrug, or a pharmaceutically acceptable solvate or salt thereof.
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Paragraph 0236-0241
(2019/01/09)
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- Design, Synthesis and Biological Evaluation of a New Series of 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea Derivatives as Antiproliferative Agents
-
To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC50 value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents.
- Zhang, Chuanming,Tan, Xiaoyu,Feng, Jian,Ding, Ning,Li, Yongpeng,Jin, Zhe,Meng, Qingguo,Liu, Xiaoping,Hu, Chun
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-
- Synthetic method of medical intermediate semi-carboamidrazone
-
The invention discloses a synthesis method of medical intermediate semicarbazone. According to a method, the semicarbazone is synthesized by taking dichloroethane, triphosgene, m-trifluoromethyl aniline, phenyl isonitrile, hydrazine hydrate, N-(3-trifluoromethyl phenyl)-semicarbazide and thiophene-2-formaldehyde as main raw materials and using the N-(3-trifluoromethyl phenyl)-semicarbazide. Aftersulfo group modified-SZ@SBA-15-SO3H catalyst is added, thiophene-2-formaldehyde is added, so that sediments are produced immediately; a thiophene ring is a five-atom and six-electron conjugate structure; after thiophene-2-formaldehyde-N(4)-m-trifluoromethyl phenyl semicarbazone is generated under the catalytic action, as -CN and the thiophene ring form conjugation, electrons are more dispersive and more stable; the semicarbazone preparation method has the characteristics of simplicity, feasibility, short preparation period and the like; the raw materials and the catalyst which are used in a technological process are high in efficiency, simple, convenient, easy to recycle, regenerable, extremely environmentally friendly and wide in application range, and has an excellent catalysis effect onsemicarbazone synthesis reaction.
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Paragraph 0014-0016; 0046-0049
(2019/08/07)
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- Synthesis and nematicidal activity of piperazinedione derivatives based on the natural product Barettin
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Nematodes are serious constraints of crop production worldwide. However, the traditional nematicides suffer from the side-effects, including environmental and human toxicity. Herein, more than 70 novel piperazinedione derivatives based on the natural product Barettin were synthesized and evaluated against the root-knot nematode Meloidogyne incognita (M. incognita). While most of synthesized compounds exhibited certain nematicidal activity at high concentration, the best one showed a nematicidal activity of 75% at 2.4 μmol/L.
- Sun, Haiyang,Li, Hui,Wang, Jiayi,Song, Gonghua
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p. 977 - 980
(2017/11/16)
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- Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase
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Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.
- Shi, Zhi-Hao,Liu, Feng-Tao,Tian, Hao-Zhong,Zhang, Yan-Min,Li, Nian-Guang,Lu, Tao
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p. 4735 - 4744
(2018/08/21)
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- Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors
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VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.
- Sun, Ying,Shan, Yuanyuan,Li, Chuansheng,Si, Ru,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 373 - 385
(2017/10/16)
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- Design, synthesis and biological evaluation of urea-based benzamides derivatives as HDAC inhibitors
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A new class of urea-based benzamides derivatives were designed and synthesized as histone deacetylases inhibitors. Biological evaluations of these compounds included the inhibitory activity of histone deacetylases1 and cytotoxicity against different cancer cell lines in vitro. Most compounds exhibited potential histone deacetylases inhibitory activity and antitumor activities. Compound 5h behaved as potent histone deacetylases1 inhibitor (IC50 = 0.182 μM) and showed comparable cytotoxicity with MS-275, which could be considered as a potential candidate compound for further development.
- Zhu, Yong,Chen, Xin,Ran, Ting,Niu, Jiaqi,Zhao, Shuang,Lu, Tao,Tang, Weifang
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p. 2879 - 2888
(2017/10/06)
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- Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4
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Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a ‘triplet’ inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.
- Li, Chuansheng,Shan, Yuanyuan,Sun, Ying,Si, Ru,Liang, Liyuan,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 506 - 518
(2017/11/14)
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- Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents
-
Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization.
- Chen, Jia-Nian,Wang, Xian-Fu,Li, Ting,Wu, De-Wen,Fu, Xiao-Bo,Zhang, Guang-Ji,Shen, Xing-Can,Wang, Heng-Shan
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-
- Discovery of novel diaryl urea derivatives bearing a triazole moiety as potential antitumor agents
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Herein, we report a novel series of diaryl urea derivatives bearing a triazole moiety, from which potent antitumor agents have been identified. With a modified triazole, most compounds showed high level activity in both cellular and enzymatic assays, accompanied with a suitable ClogD7.4 value. The most active compound, 13i, effectively suppressed proliferation of HT-29, H460 and MDA-MB-231 cancer cells, with IC50 values of 0.90, 0.85 and 1.54 μM, respectively. Compound 13i also exhibited significant inhibition of tyrosine kinases including c-Kit, RET and FLT3. Furthermore, compound 13i could obviously induce apoptosis of HT-29 cells in a concentration-dependent manner. The study of structure-activity relationships also revealed that a hydrophilic tail at the 4-position of the triazole was crucial for high activity of the compound.
- Qin, Mingze,Yan, Shuang,Wang, Lei,Zhang, Haotian,Zhao, Yanfang,Wu, Shasha,Wu, Di,Gong, Ping
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-
- From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
-
Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.
- Zhang, Chun-Hui,Chen, Kai,Jiao, Yan,Li, Lin-Li,Li, Ya-Ping,Zhang, Rong-Jie,Zheng, Ming-Wu,Zhong, Lei,Huang, Shen-Zhen,Song, Chun-Li,Lin, Wan-Ting,Yang, Jiao,Xiang, Rong,Peng, Bing,Han, Jun-Hong,Lu, Guang-Wen,Wei, Yu-Quan,Yang, Sheng-Yong
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supporting information
p. 9788 - 9805
(2016/11/19)
-
- Design, synthesis and structure-activity relationships of novel diaryl urea derivatives as potential EGFR inhibitors
-
Two novel series of diaryl urea derivatives 5a-i and 13a-l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a-i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 μM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 μM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.
- Jiang, Nan,Bu, Yanxin,Wang, Yu,Nie, Minhua,Zhang, Dajun,Zhai, Xin
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-
- With anti-tumor effect of a quinazoline-urea derivative and its application (by machine translation)
-
The present invention relates to a of the general formula (II) anti-tumor function of said quinazoline-urea derivative and its application. The definition of the substituent in the general formula (II) in the specification. This invention, in order to SUO draw non-Buddhist nun and Geftinat compounds as the precursor, retention of SUO draw non-Buddhist nun the pharmocology-carbamido; at the same time, such as in reserved [...] EGFR-TKIs Geftinat, synthesis, and obtain a series of quinazoline-urea derivatives, by the in vitro activity tests, some compounds exhibit excellent anti-tumor activity, such derivatives have high research and utility value. (II). (by machine translation)
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Paragraph 0139-0142; 0169
(2016/11/02)
-
- UREA AND BIS-UREA BASED COMPOUNDS AND ANALOGUES THEREOF USEFUL IN THE TREATMENT OF ANDROGEN RECEPTOR MEDIATED DISEASES OR DISORDERS
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Urea-based and bis-urea based compounds and analogues thereof are disclosed. These compounds are useful in the treatment of androgen-dependent diseases or disorders and androgen receptor-mediated diseases or disorders. Specifically, the compounds are useful in the treatment of diseases or disorders that are AR negative.
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Paragraph 0081; 0084
(2016/04/26)
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- Discovery of novel VEGFR-2 inhibitors. Part 5: Exploration of diverse hinge-binding fragments via core-refining approach
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Pathological angiogenesis plays a critical role in numerous diseases including malignancy. VEGFR-2 is the central regulators in angiogenesis and has become a promising target for anticancer drug design. We have identified a novel biphenyl-aryl urea incorporated with salicyladoxime (BPS-7) as potent VEGFR-2 inhibitor. As a continuation to our previous research, various aromatic-heterocyclic were introduced as hinge-binding fragment via a core-refining approach. Interestingly, many compounds exhibited comparable VEGFR-2 inhibition to Sorafenib. In particular, 12e and 12o displayed excellent VEGFR-2 inhibitory activity with IC50 values of 0.50 nM and 0.79 nM, respectively. Several title compounds showed considerable antiproliferative activity against A549 and SMMC-7721 cells. In addition, molecular docking was performed to rationalize the efficiency of the better compounds. These results will be instructive for further inhibitor design and optimization.
- Shan, Yuanyuan,Gao, Hongping,Shao, Xiaowei,Wang, Jinfeng,Pan, Xiaoyan,Zhang, Jie
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-
- N-fluorinated phenyl-N′-pyrimidyl urea derivatives: Synthesis, biological evaluation and 3D-qsar study
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With the increase of herbicide-resistant weeds, novel, more selective and even more potent herbicides to control weeds are needed. In this paper, a series of N-fluorinated phenyl-N′-pyrimidyl urea derivatives were synthesized and screened for their herbicidal activities against Amaranthus retroflexus (AR) and Setaria viridis (SV). Compound 25 (N-(3-trifluoromethylphenyl)-N′-(2- amino-4-chloro-6-methylpyrimidyl) urea) exhibited marked herbicidal activity against SV (IC50 = 11.67 mg/L) and is more potent than bensulfuron (IC50 = 27.45 mg/L), a commercially available herbicide. A statistically significant CoMFA model with high prediction abilities (q 2 = 0.869, r2 = 0.989) was obtained.
- Yue, Xia-Li,Li, Hu,Liu, Shuang-Shuang,Zhang, Qing-Ye,Yao, Jing-Jing,Wang, Fei-Yan
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p. 1069 - 1072
(2014/08/18)
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- Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo
-
We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish- based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin -4-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.
- Yang, Ling-Ling,Li, Guo-Bo,Ma, Shuang,Zou, Chan,Zhou, Shu,Sun, Qi-Zheng,Cheng, Chuan,Chen, Xin,Wang, Li-Jiao,Feng, Shan,Li, Lin-Li,Yang, Sheng-Yong
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supporting information
p. 1641 - 1655
(2013/04/10)
-
- Novel leucine ureido derivatives as inhibitors of aminopeptidase N (APN)
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Aminopeptidase N (APN/CD13) over expressed on tumor cells, plays a critical role in tumor invasion, metastasis, and tumor angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 8c had the most potent inhibitory activity against APN with the IC 50 value to 0.06 ± 0.041 μM, which could be used for further anticancer agent research.
- Ma, Chunhua,Jin, Kang,Cao, Jiangying,Zhang, Lei,Li, Xiaoguang,Xu, Wenfang
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p. 1621 - 1627
(2013/04/24)
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- Synthesis and in vitro antitumor activity of novel diaryl urea derivatives
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A series of novel diaryl ureas containing 4-[(2-amino-6-trifluromethyl) pyrimidine-4-yl]piperazine-1-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib, some compounds showed more potent and a broader spectrum of anti-cancer activities. Among them, compound 2p demonstrated significant inhibitory activities against MDA-MB-231, HT-29 and MCF-7 cell lines with IC50 values of 0.016, 0.63, 0.001 μmol/L, respectively.
- Zhao, Yan-Fang,Liu, Zi-Jian,Zhai, Xin,Ge, Dan-Dan,Huang, Qiang,Gong, Ping
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p. 386 - 388
(2013/07/19)
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- Synthesis and herbicidal activity of amide derivatives containing thiazole moiety
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Twelve novel amide derivatives containing thiazole moiety were synthesized via a coupling reaction of [4-(substituted phenyl)thiazol-2- yl] acetonitrile and aryl isocyanates catalyzed by organic bases. Their structures were characterized by 1H NMR, FTIR, MS and elemental analysis. The preliminary bioassay indicated that these compounds exhibited moderate herbicidal activities against Echinochloa crusgalli and Amaranthus ascedense.
- Weng, Jian-Quan,Liu, Xing-Hai,Tong, Guo-Tong
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p. 2149 - 2152
(2013/05/09)
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- Acrylamide Derivative And Use Thereof In Manufacture Of Medicament
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An acrylamide derivative represented by formula (I), pharmaceutically acceptable salts and solvates thereof, as well as a medicament containing said acrylamide derivative or its pharmaceutically acceptable salts as the active ingredient, which can be used to treat disorders associated with tyrosine kinase especially Bcr-Abl, including proliferative disorders such as cancers, and inflammation and the like are provided.
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Page/Page column 26
(2012/05/20)
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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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experimental part
p. 1802 - 1806
(2011/12/22)
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- Synthesis and antiproliferative activitiy of novel diaryl ureas possessing a 4H-pyrido[1,2-a]pyrimidin-4-one group
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We herein disclose a series of novel diaryl urea derivatives possessing a 4H-pyrido[1,2-a]pyrimidin-4-one group as novel potent anticancer compounds. The structures were confirmed by IR, 1H-NMR, and MS. All the compounds were screened for their antiprofilerative activity agaist the human breast cancer cell line (MDA-MB-231). The pharmacological results indicated that most of the compounds showed moderate activity. The best of this series is compound 4c (IC50 = 0.7 μmol/L), with a potency 3.6-fold higher than Sorafenib (IC50 = 2.5 μmol/L), which was approved in 2005.
- Yao, Peng,Zhai, Xin,Liu, Dong,Qi, Bao Hui,Tan, Hai Liang,Jin, Yong Cai,Gong, Ping
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scheme or table
p. 17 - 23
(2010/07/02)
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- Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis
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The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTRinh-172) inhibits cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTRinh-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modifications in its two phenyl rings, thiazolidinone core, and core-phenyl connectors. Greatest CFTR inhibition potency was found for 3-CF3 and polar group-substituted-phenyl rings, and a thiazolidinone core. Two compounds with ～1 μM CFTR inhibition potency and solubility >180 μM (>10-fold more than CFTRinh-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease.
- Sonawane,Verkman
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body text
p. 8187 - 8195
(2009/04/11)
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- Design, synthesis, and quantitative structure-activity relationship study of herbicidal analogues of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)ones
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A series of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)one derivatives were designed, synthesized, and evaluated for their herbicidal activities where some of these compounds provided 0.8) with physicochemical parameters in this set of molecules. The herbicidal activity against B. campestris was mainly affected by the molar refractivity (MR) for R1, Taft (Es0) for R2 or R6, Verloop (Lm) for R3 or R5, and electronic parameters (Hammett's constants) for R4. The optimal MR for herbicidal activity is 0.95. The herbicidal activity against Echinochloa crus-galli was mainly related with the substituents' hydrophobic parameter. The optimal π parameters for R 1 and R4 for herbicidal activity are 0.72 and 0.68, respectively. In general, these compounds showed greater herbicidal activity toward B. campestris than E. crus-galli.
- Zhu, You-Quan,Wu, Chao,Li, Hua-Bin,Zou, Xiao-Mao,Si, Xue-Kai,Hu, Fang-Zhong,Yang, Hua-Zheng
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experimental part
p. 1364 - 1369
(2009/09/06)
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- Organosilicon synthesis of isocyanates: I. Synthesis of isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series
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A convenient synthesis of known and unknown isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series, involving silylation of starting amines with hexamethyldisilazane or chlorotrimethylsilane, followed by phosgenation of the resulting N-silyl-substituted amines. An unusual high-temperature rearrangement of 3-(methoxycarbonyl)-4,5-dimethylthiophene-2-yl isocyanate into its 5-ethyl isomer. ortho-Fluorine substituent in anilines decreases the yield of isocyanates, whereas 2,3,5,6-tetrafluorophenyl isocyanate exists for only a short time as a 5% toluene solution. Pleiades Publishing, Inc. 2006.
- Lebedev,Lebedeva,Sheludyakov,Ovcharuk,Kovaleva,Ustinova
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p. 110 - 115
(2008/01/27)
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- Synthesis of new substituted 6-ureidopurines and 6-ureido-9-(2,3,5-triacetyl ribofuranosyl)purines having cytokinin (plant growth promoting) activity
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Substituted 6-ureidopurines 6a-j and 6-ureido-9-(2,3,5-triacetylribofuranosyl) purines 7a-j have been synthesized by condensing substituted phenyl isocyanates with adenine 3 and 2,3,5-triacetyladenosine 5 respectively in pyridine. Substituted phenyl isocyanates 2a-j are prepared from substituted anilines 1a-j in the presence of triphosgene and triethylamine in dry benzene. Compounds 6a-j and 7a-j have been evaluated for cytokinin activity on seeds of Raphanus sativus, family Brassicaceae (common name white radish) at 5 different concentrations in distilled water ranging from 0.001 to 10 mg litre-1. Compounds 6a, 7a, 7b and 7i having substitutents at 3 position of phenyl ring are found to show higher cytokinin activity than benzyladenine at all concentrations (Table II).
- Mhatre, Vandana,Joshi, Vidya
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p. 2667 - 2675
(2007/10/03)
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- A facile method for preparation of aromatic isocyanates using bis(trichloromethyl)carbonate
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A facile synthesis of aromatic isocyanates using bis(trichloromethyl)carbonate (BTC) is reported with high yields of products. BTC is used to supply phosgene in situ in stoichiometric amounts.
- Xu, Zhenyuan,Du, Xiaohue,Su, Weike
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p. 962 - 963
(2007/10/03)
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- Synthesis of new substituted sulfonylhydrazinecarboxamides and sulfonylhydrazinecarbothioamides having antifungal and antibacterial activities
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p-Toluenesulfonylhydrazide 3 on condensation with substituted phenyl isocyanates 2a-i and substituted phenyl isothiocyanates 2j-p gives N, 2-disubstituted sulfonylhydrazinecarboxamides 4a-i and N, 2-disubstituted sulfonylhydrazinecarbothioamides 4j-p respectively. Compounds 4a-p have been found to be bactericidal against S. aureus and S. lyphi while compound 4n shows fungicidal activity against T. mentagrophytes and T. rubrum.
- Nalavde,Joshi
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- Synthesis of new fluorine substituted hydrazinecarboxamides and hydrazine carbothioamides having antitubercular and fungicidal activity
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3-(Trifluoromethyl)phenylhydrazine 3 on condensation with substituted phenylisocyanates 2a-f and phenylisothiocyanates 2g-1 gives N,2-diphenylhydrazinecarboxamides 4a-f and N,2-diphenylhydrazine carbothioamides 4g-1 which have been found to show antitubercular and antifungal activity.
- Madhukar Nalavde,Joshi
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p. 634 - 637
(2007/10/03)
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- On the chemistry of pyrido[1,2-a]pyrazines - Reactivity towards heterocumulenes and ketenes
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In order to extend the ring transformation reactions of pyrido[1,2-a]pyrazines 1 which contain a cyclic 2-aza-1,3-diene substructure acceptor-substituted heterocumulenes 2 have been tested as dienophiles. In contrast to other reactions described to date, exclusively the exocyclic imino function was attacked. In the course of a hetero-metathesis the new aryl-(4-thiono-4H-pyrido[1,2-a]pyrazin-3-yl)amines 4Ra and aryl-(4-selono-4H-pyrido[1,2-a]pyrazin-3-yl)amines 4Rb were formed. In the case of isocyanates of type 2e and 2f the preliminary [2+2]-cycloaddition reaction preferably takes place on the C-N-bond of the isocyanate group leading to acyl-aryl substituted pyridopyrazines 4Re and 4Rf. The reaction of 1 with in situ generated ketenes of type 6 gave the pyrrolo-condensed pyrido[1,2-a]pyrazine 9 which can further be transformed to the highly substituted pyridopyrrolinones 10 . Whereas acetyl chloride only led to N-acylated pyrido[1,2-a]pyrazines 12, benzoyl chloride in addition to 12 astonishingly formed the double-acylated pyrido[1,2-a]pyrazines 13. Wiley-VCH Verlag GmbH, 1999.
- Billert, Thomas,Beckert, Rainer,Doering, Manfred,Goerls, Helmar
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p. 332 - 341
(2007/10/03)
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- Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity
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The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4- yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log K(i) values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Stark, Holger,Purand, Katja,Ligneau, Xavier,Rouleau, Agnès,Arrang, Jean-Michel,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
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p. 1157 - 1163
(2007/10/03)
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- Inactivation of Leukocyte Elastase by Aryl Azolides and Sulfonate Salts. Structure-Activity Relationship Studies
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The inhibitory activity of a series of aryl azolides and sulfonate salts toward human leukocyte elastase is reported.Several of the compounds were found to be potent inhibitors of the enzyme.Active compounds were obtained only when the specificity group and the reactive moiety were separated by a two-carbon chain.The introduction of hydrophobic groups enhanced the inhibitory activity of these compounds, with the exception of the sulfonate salts.The nature of the leaving group had had a profound effect on inhibitory activity, with compounds 23 and 26 being the most active (kobsd/ = 11722 and 13500 M-1 s-1, respectively).
- Groutas, W. C.,Brubaker, M. J.,Zandler, M. E.,Mazo-Gray, V.,Rude, S. A.,et al.
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p. 1302 - 1305
(2007/10/02)
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- THERMAL DECOMPOSITION OF SUBSTITUTED UREAS
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The thermal dissociation of N,N'-diaryl- and N,N-dimethyl-N'-aryl-ureas was investigated under isothermal conditions in absence of solvent.In the case of N,N-dimethyl-N'-arylureas enthalpies of reaction were determined, and their relation to Hammett ? constants was shown.
- Chimishkyan, A. L.,Svetlova, L. P.,Leonova, T. V.,Gluyaev, N. D.
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p. 1317 - 1320
(2007/10/02)
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