Design, synthesis and biological evaluation of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)benzoyl hydrazide derivatives as thymidylate synthase (TS) inhibitors and as potential antitumor drugs

Li, Xinyang; Liang, Jing-wei; O, Kamara Mohamed; Zhang, Tingjian; Lu, Guoqing; Meng, Fan‐hao

doi:10.1016/j.ejmech.2018.05.020

Cited by 20 publications

(14 citation statements)

References 22 publications

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“…Compounds which are structural analogues of thymidylate synthase substrates, such as 5-fluorouracil, combine with TS to form inactive complexes. This leads to the depletion of thymidylic acid in the cells, which results in the inhibition of their division and ultimately death [59,60]. DNA synthesis in cancer cells is higher than in normal cells; therefore, thymidylate synthase inhibitors constitute an important group of anti-cancer drugs.…”

Section: Anti-proliferative Effects Of 134-oxadiazole Derivativesmentioning

confidence: 99%

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

2018

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Compounds containing 1,3,4-oxadiazole ring in their structure are characterised by multidirectional biological activity. Their anti-proliferative effects associated with various mechanisms, such as inhibition of growth factors, enzymes, kinases and others, deserve attention. The activity of these compounds was tested on cell lines of various cancers. In most publications, the most active derivatives of 1,3,4-oxadiazole exceeded the effect of reference drugs, so they may become the main new anti-cancer drugs in the future.

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Section: Anti-proliferative Effects Of 134-oxadiazole Derivativesmentioning

confidence: 99%

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

2018

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“…Briefly, various substituted benzoic acids ( 1a-1 m ) were reacted with thionyl chloride to obtain intermediates ( 2a-2 m ) [20] . The commercially available methyl 3-nitrobenzoate ( 3 ) and hydrazine monohydrate were refluxed in methanol to obtain the corresponding compound ( 4 ) [4] , [21] . Performed One-pot synthesis of critical intermediates ( 5a-5 m ) from compounds ( 2a-2 m ) and 4 , and there are many ways to synthesis the oxadiazoles in the synthesis reaction [22] , [23] .…”

Section: Resultsmentioning

confidence: 99%

“…The 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonyl chloride and compound ( 6a-6 m ) underwent the Hinsberg reaction under alkaline conditions, and the target compounds ( 7a-7 m ) were obtained [27] , [28] . Preparation of the critical intermediate 2,4-dihydroxypyrimidine-5-sulfonyl chloride is described in detail in our previous research [4] , [5] .…”

Section: Resultsmentioning

confidence: 99%

“…Tumor cells are capable of releasing angiogenic factors and inducing paravascular angiogenesis [3] . In our previous work, a series of derivatives based on uracil was reported [4] , [5] . Among these, the structure of (N-phenyl- (2,4-dihydroxypyrimidine-5-sulfonamido) phenylephrine derivative) had the potential to inhibit VEGF secretion, which in turn could inhibit tumor angiogenesis, this finding that suggests that this bone structure had excellent value ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC

Wang

et al. 2020

Journal of Advanced Research

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“…In our previous studies, we reported a series of TS inhibitors based on N -phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)benzoyl hydrazide skeleton with IC 50 values around 10–20 μM. And compound 10l , the most potent one in the series, had excellent anti-proliferation ability (IC 50 = 1.26 μM, against A549 cells), which were superior to pemetrexed in the treatment of non-small cell lung cancer (NSCLC) cell 6 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity

Zhang

Kamara

et al. 2019

Cell Death Dis

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Thymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N -phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC 50 = 0.67 μM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.

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Design, synthesis and biological evaluation of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)benzoyl hydrazide derivatives as thymidylate synthase (TS) inhibitors and as potential antitumor drugs

Cited by 20 publications

References 22 publications

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC

Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity

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