Synthesis and biological evaluation of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives as potential BRAFV600E inhibitors

Yao, Jing; Ji, Jianfeng; Yang, Jun; Xiang, Tie; Zhou, Changkai

doi:10.1007/s00044-017-1957-z

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…However, A-RAF exhibits the weakest influence among the other RAF isoforms toward MEK activation [ 13 , 14 ]. Therefore, medicinal chemistry research on RAF kinase inhibitors is focused on designing new molecules that can inhibit such oncogenic proteins, particularly the mutant forms [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Quinoline-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity

Kim

Park

Seo

et al. 2023

IJMS

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The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines 17b and 18a stood out as the most potent members, with IC50 values of 0.128 µM, 0.114 µM against B-RAFV600E, and 0.0653 µM, 0.0676 µM against C-RAF. Most importantly, 17b elicited remarkable inhibitory potency against the clinically resistant B-RAFV600K mutant with an IC50 value of 0.0616 µM. The putative binding mode of 17b and 18a were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline VII against all cell lines at a 10 µM dose. Notably, both 17b and 18b showed highly potent antiproliferative activity against melanoma cell lines with growth percent under −90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while 17b maintained potency with GI50 values of 1.60–1.89 µM against melanoma cell lines. Taken together, 17b, a promising B-RAFV600E/V600K and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics.

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Section: Introductionmentioning

confidence: 99%

Discovery of New Quinoline-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity

Kim

Park

Seo

et al. 2023

IJMS

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Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

et al. 2023

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Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF V600 ), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/ OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

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Recent Advances in Biological Active Sulfonamide based Hybrid Compounds Part A: Two-Component Sulfonamide Hybrids

Ghomashi

Aghaei

et al. 2023

CMC

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Sulfonamides constitute an important class of drugs, with many types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, anti-obesity, diuretic, hypoglycemic, antithyroid, antitumor, and anti-neuropathic pain activities. The sulfonamides have the general formula R-SO2NHR', in which the functional group is bound to an aromatic, heterocycle, aliphatic, and so on. The nature of the R and R' moiety is variable, starting with hydrogen and ranging to a variety of moieties incorporating organic compounds such as coumarin, isoxazole, tetrazole, pyrazole, pyrrole, and so many other pharmaceutical active scaffolds that lead to a considerable range of hybrids named as sulfonamide hybrids. Part A of this review presents the most recent advances in designing and developing two-component sulfonamide hybrids containing coumarin, indole, quinoline, isoquinoline, chalcone, pyrazole/pyrazoline, quinazoline, pyrimidine, thiazole, benzothiazole, and pyridine between 2015 and 2020. Specifically, the authors review the scientific reports on the synthesis and biological activity of this kind of hybrid agent.

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Synthesis and biological evaluation of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives as potential BRAFV600E inhibitors

Cited by 3 publications

References 25 publications

Discovery of New Quinoline-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity

Discovery of New Quinoline-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

Recent Advances in Biological Active Sulfonamide based Hybrid Compounds Part A: Two-Component Sulfonamide Hybrids

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