Synthesis, structure analysis, antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives

Rao, Guo‐Wu; Wang, Cui; Wang, Jian; Zhao, Zhiwei; Hu, Wei‐Xiao

doi:10.1016/j.bmcl.2013.09.036

Cited by 16 publications

(4 citation statements)

References 22 publications

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“…1,2,3,4‐Tetrazines with thermally unstable structures can be combined with five or six membered rings as well as oxides to increase their stability (Ram et al, 2019) The synthesis of these heterocyclic compounds and their derivatives, due to their a various biological and medicinal properties, are desirable synthetic targets (Wan et al, 2019). One of the isomers, 1,2,4,5‐tetrazine, does possess a stable structure and exhibits broader biological activity such as antibacterial, antitumor, anti‐inflammatory, anti‐malarial, and antiviral (Rao et al, 2013; Nhu et al, 2010; Tabassum et al, 2012; Sauer, 1996). Moreover, there are several studies in the literature concerned with the pharmaceutical use of compounds with 1,2,3,4‐tetrazine skeletons (Almerico et al, 2005; Hu et al, 2005; Neunhoeffer, 1985; Zlotin et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of novel 1,2,3,4‐tetrazines as new anti‐leukemia cancer agents

Eyilcim,

Gunay,

Gunkara

et al. 2023

Chem Biol Drug Des

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A series of novel 1,2,3,4‐tetrazines were designed and synthesized. 1H‐NMR spectroscopy, 13C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm‐6, Reh, K562, and Molt‐4) and one non‐leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm‐6, K562, Jurkat, and Molt‐4 cell lines, IC50 values were found to be 15.98, 19.12, 23.15, and 25.80 μM, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4‐tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents.

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Section: Introductionmentioning

confidence: 99%

Design and synthesis of novel 1,2,3,4‐tetrazines as new anti‐leukemia cancer agents

Eyilcim,

Gunay,

Gunkara

et al. 2023

Chem Biol Drug Des

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“…[5][6][7] In the last decades, a large number of 1,2,4,5-tetrazine derivatives have been synthesized and their antitumor activity has been reported, which has led to them emerging as a promising and attractive scaffolds. [8][9][10][11] Among them, a 1,4-dihydro-1,2,4,5-tetrazine derivative, N,N′-di (m-methylpheny)-3,6-dimethyl-1,4-dihydro-1,2,4, 5-tetrazine-1,4-dicarboamide (ZGDHu-1), has been found with strong inhibition on the proliferation of PANC-1 pancreatic cancer cells via apoptosis and G2/M cell cycle arrest; 12 3-alkylamino-1,2,4,5-tetrazine derivative I exhibits potent antiproliferative activity against H1975 cells; 13 and 3-(4-methylimidazole-1-yl)imidazo [1,2-b] [1,2,4,5]tetrazine (II), an imidazotetrazine derivative, is being used for therapy of malignant tumors in human and animals (Figure 1). 14 Our research group has synthesized numerous [1,2,4] triazolo [4,3-b] [1,2,4,5]tetrazine derivatives, and some of them (TZXU-1-3) showed potent antiproliferative activities against MCF-7, Bewo, and HL-60 cells and c-Met kinase inhibitory activities (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel 6-alkoxy-3-aryl-[1,2,4]triazolo[4,3-b][1,2,4,5] tetrazines

Shi

Yang

Ye-tao

et al. 2019

Journal of Chemical Research

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A series of 6-alkoxy-3-aryl-[1,2,4]triazolo[4,3- b][1,2,4,5] tetrazine derivatives is synthesized and evaluated for their antitumor activities. These compounds exhibit potent antiproliferative activities against A549, Bewo, and MCF-7 cells. Molecular docking is performed to study the inhibitor–c-Met kinase interactions, and the results show that 6-ethoxyl-3-phenylethyl-[1,2,4]triazolo[4,3- b][1,2,4,5] tetrazine is potently bound to c-Met kinase with two hydrogen bonds and one π–π interaction. Based on these preliminary results, it is thought that compound 6-ethoxyl-3-phenylethyl-[1,2,4]triazolo[4,3- b][1,2,4,5] tetrazine with potent inhibitory activity may be a potential anticancer agent.

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“…Among the three isomers, 1,2,4,5-tetrazines are the most stable compounds, and 1,2,4,5-tetrazine derivatives have demonstrated potential therapeutic properties, such as anti-mite ( 5 ), herbicidal ( 6 ), anti-malarial ( 7 ), antiviral ( 6 ), anti-inflammatory ( 6 ), antibacterial ( 8 ) and antitumor activities ( 6 , 9 ). Furthermore, 1,2,4,5-tetramethyl-3,6-bis (phenylethynyl)-1,2,4,5-tetrazine was one of the first 1,2,4,5-tetrazine derivatives to be identified as possessing antitumor activity ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

“…Hu (Pharmaceutical College of Zhejiang University of Technology, Hangzhou, China). Among these tetrazine compounds, the derivative N,N'-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) was identified to exhibit the highest antitumor activity ( 6 , 10 – 12 ). Its structure is shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

ZGDHu‑1 for cancer therapy (Review)

et al. 2017

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N,N'-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) is a novel tetrazine derivative that was initially designed and produced by Professor W.X. Hu, and which has been reported by our group to exhibit antitumor activity. Accumulating evidence suggests that the anticancer mechanisms of ZGDHu-1 may be involved indifferent biological activities, particularly in acute myeloid leukemia (AML) cells. At a high concentration, ZGDHu-1 has been demonstrated to inhibit the proliferation of the leukemia cells by arresting the cell cycle at the G2/M phase, and by inducing cell apoptosis via inducing the accumulation of reactive oxygen species, the translocation of phosphatidylserine across the plasma membrane and the loss of mitochondrial membrane potential. Furthermore, at a low concentration, it was demonstrated to induce the differentiation and degrade the AML1-eight-twenty-one fusion protein in AML cells. Finally, results from a previous study indicate that ZGDHu-1 is a potential proteasome inhibitor. Overall, our preliminary research suggests that ZGDHu-1 may be a promising anticancer drug; however, further research is warranted to identify the exact drug target and potential clinical application in leukemia cells or solid tumors. In the present review, the application of ZGDHu-1 in cancer research, in addition to the specific underlying targets of ZGDHu-1, are discussed.

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Synthesis, structure analysis, antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives

Cited by 16 publications

References 22 publications

Design and synthesis of novel 1,2,3,4‐tetrazines as new anti‐leukemia cancer agents

Design and synthesis of novel 1,2,3,4‐tetrazines as new anti‐leukemia cancer agents

Synthesis and biological evaluation of novel 6-alkoxy-3-aryl-[1,2,4]triazolo[4,3-b][1,2,4,5] tetrazines

ZGDHu‑1 for cancer therapy (Review)

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