- Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer
-
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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-
- 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
-
-
- Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions
-
Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01–TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 μM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.
- Cheng, Minghui,Meng, Xin,Tang, Haikang,Xu, Wenqing,Yang, Fujun,Zhang, Yuan
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p. 344 - 353
(2019/12/30)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
-
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
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-
Page/Page column 253-254
(2020/12/30)
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- Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus
-
Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
- Ruan, Banfeng,Zhang, Yuezhou,Tadesse, Solomon,Preston, Sarah,Taki, Aya C.,Jabbar, Abdul,Hofmann, Andreas,Jiao, Yaqing,Garcia-Bustos, Jose,Harjani, Jitendra,Le, Thuy Giang,Varghese, Swapna,Teguh, Silvia,Xie, Yiyue,Odiba, Jephthah,Hu, Min,Gasser, Robin B.,Baell, Jonathan
-
supporting information
(2020/02/04)
-
- Design, synthesis and antitumor assessment of phenylureas bearing 5-fluoroindolin-2-one moiety
-
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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- Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
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Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinyl-arylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc?/GPx4/ROS and PI3K/Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents’ discovery.
- Chen, Jia-Nian,Li, Ting,Cheng, Li,Qin, Tai-Sheng,Sun, Ye-Xiang,Chen, Chu-Ting,He, Yue-Zhen,Liu, Guang,Yao, Di,Wei, Ying,Li, Qiu-Yin,Zhang, Guang-Ji
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-
- Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based diaryl urea derivatives for suppressing VEGFR-2 signaling
-
A novel structural series of tetrahydroisoquinoline-based compounds that incorporate the diaryl urea moiety was designed, synthesized, and biologically evaluated as suppressors of VEFGR-2 signaling. As a consequence, compounds 9k and 9s exhibited comparable or superior cytotoxic activity to that of gefitinib against the tested three cell lines, including A549, MCF-7, and PC-3. Importantly, both of them downregulated the expression of VEGFR-2, and inhibited VEGFR-2 phosphorylation at the concentration of 0.5 or 1.0 μmol/l. Besides, they suppressed human umbilical vein endothelial cell tube formation at the concentration of 4.0 μmol/l. Considering their capability of down-regulating VEGFR-2 expression and inhibiting VEGFR-2 phosphorylation, 9k and 9s may serve as suppressors of angiogenesis for further investigation.
- Huang, Yuanzheng,Zhang, Yang,Li, Jiaming,Ma, Xiaodong,Hu, Mengqi,Yang, Yu,Gao, Sufan
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p. 508 - 516
(2019/05/14)
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- Phenylquinoline transient receptor potential vanilloid 1 antagonists for the treatment of pain: Discovery of 1-(2-phenylquinoline-4-carbonyl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide
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Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl–phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 10.2 nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.
- Liao, Chen,Liu, Yan,Liu, Chunxia,Zhou, Jiaqi,Li, Huilan,Wang, Nasi,Li, Jieming,Liu, Taiyu,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai
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p. 845 - 854
(2018/01/10)
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- Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents
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Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.
- Li, Shu,Li, Gongming,Yang, Xiaohong,Meng, Qian,Yuan, Shuo,He, Yun,Sun, Dequn
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supporting information
p. 2275 - 2278
(2018/05/24)
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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 and Synthesis of 4-Alkylidene-β-lactams: Benzyl- and Phenethyl-carbamates as Key Fragments to Switch on Antibacterial Activity
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The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a β-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-β-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate β-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2–4 mg L?1.
- Giacomini, Daria,Martelli, Giulia,Piccichè, Miriam,Calaresu, Enrico,Cocuzza, Clementina Elvezia,Musumeci, Rosario
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p. 1525 - 1533
(2017/09/25)
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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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- With anti-tumor effect of a quinazoline-urea derivative and its application (by machine translation)
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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; 0170
(2016/11/02)
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- Synthesis and antibacterial activity of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives
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A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives (6a-h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus (MIC 50 =0.031-2 μg ml -1) except 6g and Methicillin-sensitive S. epidermidis (MIC 50 =0.031-0.5 μg ml -1). MIC 90 of 6d against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular, compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus.
- Zheng, Zhonghui,Du, Deping,Cao, Lili,Liu, Jun,Chen, Xiaofang
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p. 811 - 817
(2016/12/07)
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- Syntheses of isocyanates via amines and carbonyl fluoride
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Isocyanates are widely used in many different areas, but the most common synthesis route-phosgene route cannot fit the more and more rigorous restriction of safety and environment. Here, a facile synthesis method of isocyanates via amines and carbonyl fluoride is proven feasibly by expanding its applications to the syntheses of nine different isocyanates. And two differences with the phosgene route are proposed. The reaction could occur under milder conditions and afford isocyanates in good yields, especially for the isocyanates containing electron withdrawing groups. It is appealing for industrial application.
- Quan, Hengdao,Zhang, Ni,Zhou, Xiaomeng,Qian, Hua,Sekiya, Akira
-
-
- Rhenium-catalyzed C-H aminocarbonylation of azobenzenes with isocyanates
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The first C-H aminocarbonylation of azobenzenes with isocyanates is achieved by using rhenium-catalysis, which provides an expedient and atom-economical access to varied o-azobenzamides from readily available starting materials. The reaction efficiency can be enhanced by the catalytic use of sodium acetate via accelerated C-H bond activation.
- Geng, Xiaoyu,Wang, Congyang
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supporting information
p. 7619 - 7623
(2015/07/15)
-
- 4-POSITION SUBSTITUTED PYRAZOLOPYRIMIDINE DERIVATIVE, AND USE THEREOF IN DRUG PREPARATION
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The invention belongs to the technical field of organic synthetic drugs, and particularly relates to a pyrazolopyrimidine derivative and a preparation method and medical uses thereof. The invention provides a new pyrazolopyrimidine derivative mainly having position 4 substituted, i.e., position substituted by Y in formula I. The pyrazolopyrimidine derivative of the invention has a structural formula I as follows: The invention provides a new pyrazolopyrimidine derivative and a simple, efficient and low-cost preparation method thereof. The pyrazolopyrimidine derivative of the invention has good inhibitory activity for multiple kinases, has inhibitory action on multiple solid tumors, leukemia and autoimmune diseases, provides a new effective choice for preparation of kinase inhibitors, medicines for autoimmune diseases, angiogenesis inhibitors and antitumor drugs, and has good application prospect.
- -
-
Paragraph 0105
(2015/07/15)
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- Oxime carbamates as potential insecticidal agents: Design, synthesis and biological evaluation
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A series of oxime carbamates derivatives were designed and synthesized as a part of our ongoing search for novel high potential agrochemicals. Their structures were confirmed by 1H NMR, 13C NMR and elemental analysis. The bioassays results indicated that some of the obtained compounds exhibited good insecticidal activity against Heliothis armigera and Plutella xylostella.
- Ke, Shaoyong,Yang, Ziwen,Shi, Liqiao,Liu, Manli,Liang, Ying,Wang, Kaimei,Long, Tong,Jiang, Aibing,Zhang, Zhigang
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p. 771 - 777
(2015/10/05)
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- N-substituted 2-isonicotinoylhydrazinecarboxamides-new antimycobacterial active molecules
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This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4- octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl) hydrazinecarboxamide (MIC = 4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria. gfjh+l;kfldf.
- Rychtarcikova, Zuzana,Kratky, Martin,Gazvoda, Martin,Komloova, Marketa,Polanc, Slovenko,Kocevar, Marijan,Stolarikova, Jirina,Vinsova, Jarmila
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p. 3851 - 3868
(2014/05/20)
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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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- 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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- Discovery of hybrid dual N-acylhydrazone and diaryl urea derivatives as potent antitumor agents: Design, synthesis and cytotoxicity evaluation
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Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications.
- Zhai, Xin,Huang, Qiang,Jiang, Nan,Wu, Di,Zhou, Hongyu,Gong, Ping
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p. 2904 - 2923
(2013/05/09)
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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
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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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p. 1641 - 1655
(2013/04/10)
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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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- Palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate: A practical synthesis of unsymmetrical ureas
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An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate is reported. The protocol allows for the synthesis of unsymmetrical N,N'-di- and N,N,N'-trisubstituted ureas in one pot and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive elimination steps of the reaction, including the first demonstration of reductive elimination from an arylpalladium isocyanate complex to produce an aryl isocyanate.
- Vinogradova, Ekaterina V.,Fors, Brett P.,Buchwald, Stephen L.
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supporting information; experimental part
p. 11132 - 11135
(2012/08/28)
-
- (Tosylimino)phenyl-λ3-iodane as a reagent for the synthesis of methyl carbamates via hofmann rearrangement of aromatic and aliphatic carboxamides
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A new, mild procedure for the Hofmann rearrangement of aromatic and aliphatic carboxamides using (tosylimino)phenyl-λ3-iodane, PhINTs, as a reagent is reported. Because of the mild reaction conditions, this method is particularly useful for the Hofmann rearrangement of substituted benzamides, which usually afford complex reaction mixtures with other hypervalent iodine oxidants. The mild reaction conditions and high selectivity in the reaction of carboxamides with PhINTs allow the isolation of the initially formed labile isocyanates or their subsequent conversion to stable carbamates by treatment with alcohols.
- Yoshimura, Akira,Luedtke, Matthew W.,Zhdankin, Viktor V.
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experimental part
p. 2087 - 2091
(2012/05/05)
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- Discovery of N-benzyl-N′-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): Optimization of the amine portion
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Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
- Duan, Maosheng,Peckham, Jennifer,Edelstein, Mark,Ferris, Robert,Kazmierski, Wieslaw M.,Spaltenstein, Andrew,Wheelan, Pat,Xiong, Zhiping
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scheme or table
p. 7397 - 7400
(2011/02/23)
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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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- Novel potent and efficacious nonpeptidic urotensin II receptor agonists
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Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)- propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49).
- Lehmann, Fredrik,Pettersen, Anna,Currier, Erika A.,Sherbukhin, Vladimir,Olsson, Roger,Hacksell, Uli,Luthman, Kristina
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p. 2232 - 2240
(2007/10/03)
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- Method for using a carbamoyl fluoride as fluorinating agent
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The invention concerns a method for using a carbamoyl fluoride as fluorinating agent. Said method consists in treating a derivative bearing a halogen-containing carbon, with a carbamoyl fluoride at a temperature not less than 70° C. and in maintaining the ratio between the sum of hydrofluoric acid (HF) and carbamoyl fluoride as well as between the sum of exchangeable halogen atoms, isocyanate functions and carbamoyl fluoride [(HF+carbamoyl fluoride)/(exchangeable halogen+isocyanate+carbamoyl fluoride)] at a value not more than 1.2; then in carrying out a catalysis process with tin, antimony and/or titanium salt. The invention is applicable to synthesis of fluorinated derivatives.
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- 5-HT2A receptor inverse agonists
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Disclosed herein is a new class of pyrazole compounds which act at the 5HT2A receptors.
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- Small molecule modulators of non-endogenous, constitutively activated human serotonin receptors
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Disclosed herein are non-endogenous, constitutively activated forms of the human 5-HT2A and human 5-HT2C receptors and uses of such receptors to screen candidate compounds. Further disclosed herein are candidate compounds identified by the screening method which act at the 5HT2A receptors. Yet further disclosed is a new class of compounds which act at the 5HT2A receptors.
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- Rapid construction of isatin derivatives via addition of bis(alkylthio)carbenes to aryl isocyanates
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Thermally induced cyclization between bis(alkylthio)carbenes, derived from the corresponding oxadiazolines, and substituted aryl isocyanates provides access to a variety of isatin derivatives with good efficiency.
- Rigby, James H.,Danca, M. Diana
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p. 6891 - 6894
(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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- Pyrazolines as insecticides
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Novel pyrazolines of the formula (I) wherein A represents a phenyl group which may be substituted by at least one substituent selected from the class consisting of halogen, C1 4alkyl, C1 4alkoxy and halogeno-C1 4alkyl, or A represents halogen-substituted 3-pyridyl,B represents phenyl which may be substituted by halogen, or B represents halogen substituted 3-pyridyl,X represents hydrogen, halogen or halogeno C1 4alkyl, and, Y represents hydrogen, halogen, C1 4alkyl or halogeno-C1 4alkyl, with the proviso that X and Y do not simultaneously represent hydrogen atom, and that at least one of A and B represents halogen-substituted 3-pyridyl. The new compounds exhibit powerful insecticidal properties.
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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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