Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors

Wen-hu, Zhan; Li, Yanyang; Weiping, Huang; Zhao, Yuqin; Yao, Ziheng; Yu, Shanyou; Yuan, Si-Ming; Jiang, Falong; Yao, Shan; Li, Shuxin

doi:10.1016/j.bmc.2012.05.051

Cited by 21 publications

(15 citation statements)

References 16 publications

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“…The potency of compounds may arise from many factors, such as molecular size, electronic properties of the substituent groups and hydrogen bond formation . To investigate the structure–activity relationships (SAR) of the compounds, many different substituent groups, including aliphatic hydrocarbons and phenyl rings bearing diverse electron‐withdrawing groups or electron‐donating groups, were introduced to the 16,17‐dihydro‐gibberellin skeleton.…”

Section: Resultsmentioning

confidence: 99%

“…According to the current model of GA signaling pathway in plants, the gibberellin receptor GIBBERELLIN INSENSITIVE DWARF1 (GID1) is bound and activated by bioactive GA, which enables transcriptional regulator DELLA proteins to interact with GID1, followed by DELLAs degradation through 26S proteasome . This event eventually results in transcriptional reprogramming of GA‐responsive genes .…”

Section: Resultsmentioning

confidence: 99%

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Improved synthetic route of exo‐16,17‐dihydro‐gibberellin A5‐13‐acetate and the bioactivity of its derivatives towards Arabidopsis thaliana

Tian

Liu

et al. 2019

Pest Management Science

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BACKGROUND: The use of exo-16,17-dihydro-gibberellin A5-13-acetate (DHGA 5 ) in agriculture has been limited by its low synthetic yield. This study was aimed at optimizing the synthetic route of DHGA 5 , designing and synthesizing new derivatives with strong plant growth inhibitory activities.RESULTS: Previous synthetic methods were replaced with a shorter, milder and faster reaction route with higher yield (76.3%) of DHGA 5 . Based on this novel route, a series of new derivatives were designed and synthesized using DHGA 5 as a lead compound and characterized and evaluated for biological activities in Arabidopsis thaliana. Among the 15 tested derivatives, compound 14j showed a lower medium inhibition concentration (IC 50 , 73 M) in Arabidopsis than that of DHGA 5 (91 M). Gibberellin deficient mutant assay further revealed that 14j had very different activities compared to DHGA 5 as it specifically inhibits gibberellin biosynthetic pathways. In addition, 14j does not influence the interaction between gibberellin receptors (GID1) and the master growth repressor (RGA) based on yeast two-hybrid assay. CONCLUSION: The optimized synthetic route provides a promising method for large-scale preparation of DHGA 5 . Our biological assays indicate that 14j likely acts on gibberellin signaling elements other than GID1. These results indicate that novel plant growth regulators can be developed. Synthesis of DHGA 5 (Compound 8)The optimized synthetic route of DHGA 5 (8) is shown in Fig. 3.Synthesis of (The intermediate 2 was prepared as described previously. 26 A mixture of GA 3 (10 g, 28.88 mmol), acetic anhydride (Ac 2 O) (20 mL) and 4-dimethylaminopyridine (DMAP) (36 mg, 0.28 mmol) in anhydrous pyridine (50 mL) was stirred at room temperature (rt) for Pest Manag Sci 2020; 76: 807-817

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Improved synthetic route of exo‐16,17‐dihydro‐gibberellin A5‐13‐acetate and the bioactivity of its derivatives towards Arabidopsis thaliana

Tian

Liu

et al. 2019

Pest Management Science

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“…The results of structure–activity relationship (SAR) analyses have indicated that the pyridine facilitates a suitable chemical interaction with Cys531 in a hinge region of B-Raf kinase, while the terminal phenyl ring occupies a hydrophobic pocket. The urea moiety connects both functional groups and forms important hydrogen-bond interactions with Glu500 and Asp593 [ 7 , 8 , 9 , 10 ]. Considerable studies were conducted on modification of the urea moiety, and potent compounds were identified by introducing an amide [ 11 ], rhodanine [ 12 ], or benzimidazole [ 13 ] group.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

Yao

et al. 2017

Molecules

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Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)-N-methylpicolinamide (8f) potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.

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Section: Introductionmentioning

confidence: 99%

“…Optimization of substituents on pyridyl group has led to a variety of interesting compounds . Recently, Zhan et al reported a series of sorafenib analogs that were substituted by a trifluoromethyl imidazolyl group at the pyridyl ring instead of the methylamide fragment. Of the resulting compounds, the best exhibited an IC 50 value of 10.6 nM against CRAF, which was 2.3‐fold more active than sorafenib, and indicated that the pyridyl ring was well tolerated for heteroaryl substituents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel 4‐(2‐Fluorophenoxy)‐2‐(1H‐tetrazol‐1‐yl)pyridines Bearing Semicarbazone Moieties as Potent Antitumor Agents

Qin

Liao

et al. 2013

Archiv der Pharmazie

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A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 µM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 µM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 µM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.

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Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors

Cited by 21 publications

References 16 publications

Improved synthetic route of exo‐16,17‐dihydro‐gibberellin A5‐13‐acetate and the bioactivity of its derivatives towards Arabidopsis thaliana

Improved synthetic route of exo‐16,17‐dihydro‐gibberellin A5‐13‐acetate and the bioactivity of its derivatives towards Arabidopsis thaliana

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

Synthesis and Biological Evaluation of Novel 4‐(2‐Fluorophenoxy)‐2‐(1H‐tetrazol‐1‐yl)pyridines Bearing Semicarbazone Moieties as Potent Antitumor Agents

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