Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors

Zhai, Xin; Bao, Guanglong; Wang, Limei; Cheng, Mingke; Zhao, Meng; Zhao, Si-Jia; Zhou, Hongyang; Gong, Ping

doi:10.1016/j.bmc.2016.02.003

Cited by 26 publications

(7 citation statements)

References 27 publications

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“…In the last few years, a lot of more active and selective quinoline derivatives have been synthesized and biologically evaluated by modifying lead compounds ( Table 1 ). The most representative modifications are: (1) at position C-7 of quinoline ring system, generally with the introduction of appropriate substituents to improve solubility, (2) at the linker portion [ 34 ], that has been modified by different cyclic/acyclic 5-atoms-analogues with similar electronic features: pyridazinone-3-carboxyamide 3 [ 35 ], 3-oxo-3,4-dihydroquinoxaline 4 [ 36 ], 1H-imidazole-4-carboxamide or (E)-3-hydrosulfonylacrylamide 5 , 6 [ 37 ], 1,2,3-triazole-4-carboxamide 7 , 8 [ 38 , 39 ], 2-imidazolone-4-carboxamide 9 [ 40 ], acylhydrazone moiety 10 [ 41 ], pyridine/pyrimidine-2-carboxyamide 11 [ 42 ], 2-phenylquinoline-4-carboxamide 12 [ 33 ], 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety 13 [ 43 ], acyclic semicarbazones 14 [ 44 , 45 ], acylthiourea moiety [ 46 ], l,2,4-triazine-3,5-dione 15 [ 47 ], 1,8-naphthyridin-2-one 16 [ 48 ], 2-oxo-1,2-dihydropiridine-3-carboxamide 17 [ 49 ], 4-oxo-1,4-dihydroquinoline-3-carboxamide 18 [ 50 ], 5-(aminomethylene)pyrimidine-2,4,6-trione moiety 19 [ 51 ], 4-oxo-3,4-dihydrophthalazine-1-carboxamide 20 [ 52 ], pyrazolone 21 [ 53 ], and (thio)semicarbazone 22 [ 54 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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“…In the literature some semicarbazone derivatives are reported as protein kinase inhibitors [19,20]. Thus, this information motivated the accomplishment of the kinase testing that indicated 3c as a promising compound for further studies to determine the possible mechanism of action.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…Semicarbazones represent an important class of chemicals described in the literature with diverse biological properties such as anticonvulsant [14], antimicrobial, antinocipeptive and anti-inflammatory [15], anti-Alzheimer [16], antichagasic [17], antiproliferative, cytotoxic and pro-apoptotic activity [18], among others. The anticancer activity of semicarbazones is also known and some studies describe these compounds as protein kinase inhibitors [19,20].…”

Section: Introductionmentioning

confidence: 99%

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

et al. 2019

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Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).

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“…The biological activity of TSC metal complexes is associated with the chelating ability of TSC ligands and their facility in inducing the perturbation of intracellular metal homeostasis (in particular of iron [11,25,26] and copper [27,28]). By forming redox active complexes, they generate reactive oxygen species (ROS) able to influence the activity of enzymes such as tyrosinase [29][30][31], topoisomerase [32], kinase [33,34], ribonucleotide reductase [35] or metalloproteinase [36].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

et al. 2020

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Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.

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Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors

Cited by 26 publications

References 27 publications

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

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