- Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2
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New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.
- Sun, Shaofeng,He, Zuopeng,Huang, Mindong,Wang, Ningning,He, Zongzhong,Kong, Xiangkai,Yao, Jianwen
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p. 2381 - 2391
(2018/04/11)
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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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- 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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- 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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- 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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supporting information
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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- Method of controlling aquatic weeds
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A method of controlling aquatic weeds which comprises adding to a body of water containing the aquatic weeds a substituted 1-thiadiazolyl-3-arylurea in sufficient quantity to kill the weeds.
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