Some 1,3,5-trisubstituted pyrazoline derivatives targeting breast cancer: Design, synthesis, cytotoxic activity, EGFR inhibition and molecular docking

George, Riham F.; Kandeel, M. M.; El-Ansary, Dina Y.; Kerdawy, Ahmed M. El

doi:10.1016/j.bioorg.2020.103780

Cited by 28 publications

(21 citation statements)

References 22 publications

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“…Following the screening of 73 herbal products, Song et al found that licochalcone C, chalcones and isolicoflavonol in licorice were the key compounds critical for hCES2A inhibition, which will be very helpful in developing new herbal remedies or drugs for ameliorating hCES2A-associated drug toxicity. Molecular docking with corresponding chalcones has also been applied to predict the binding mode and explain the phenotypic activity of EGFR [ 103 , 208 ], aurora kinase [ 209 , 210 ], anaplastic xanthine oxidase (XO), the colchicine binding site of the tubulin [ 211 ], the estrogen receptor [ 212 , 213 ] and acetylcholinesterase (AChE) [ 214 ]. The advantage of using a computational strategy is the convenience of predicting the binding target(s) of chalcones before biological validation.…”

Section: Representative Mechanisms Of Anticancer Action Of Chalconesmentioning

confidence: 99%

Chalcone Derivatives: Role in Anticancer Therapy

et al. 2021

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Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

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Section: Representative Mechanisms Of Anticancer Action Of Chalconesmentioning

confidence: 99%

Chalcone Derivatives: Role in Anticancer Therapy

et al. 2021

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“…Epidermal Growth Factor Receptor (EGFR) consists of a family of four different tyrosine kinases (TKs) including EGFR (HER1), HER2, HER3 and HER4 that plays a critical role in the development of multiple cellular functions including cell growth, survival, propagation, differentiation and cell death. EGFR consists of an extracellular, a transmembrane, and an intracellular tyrosine kinase domain [4]. Upon binding of the ligands to the extracellular domain, dimerization occurs with other receptors triggering autophosphorylation of tyrosine residues with the catalytic domain thus activating downstream cell signaling pathways and subsequent signal transduction [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…N-1 atom of the quinazoline ring binds with the backbone NH of Met769, in the ATP-binding pocket, via hydrogen bonding. Similarly, a water (HOH-10) molecule-induced hydrogen bonding interaction is noticed between the N-3 atom of the quinazoline ring and Thr766 side chain [4,6,12]. The aniline ring completely occupies the adjacent hydrophobic region of the EGFR kinase domain and the free NH linker of aniline is clearly optimal [6].…”

Section: Introductionmentioning

confidence: 99%

“…EGFR consists of an extracellular, a transmembrane, and an intracellular tyrosine kinase domain [4]. Upon binding of the ligands to the extracellular domain, dimerization occurs with other receptors triggering autophosphorylation of tyrosine residues with the catalytic domain thus activating downstream cell signaling pathways and subsequent signal transduction [4,5]. There are two ways to inhibit EGFR either by blocking ligand binding to the extracellular domain with monoclonal antibodies or by small-molecule inhibitors which interact with the ATP-binding region [6].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Antitumor Activities and Molecular Modelling of 4-Anilinoquinazoline Derivatives as EGFR-TK Inhibitors

Gomaa

El‐Sayed

Selim

2022

Preprint

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New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly, derivatives 8a, 8f and 9 with IC50 values of 0.14±0.003, 0.119±0.003, and 0.115±0.002 μM, respectively, showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3 and LS-174T cell lines. Multikinase enzymes inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK which also had resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell cycle analyses of MCF-7 cells treated with 8a and 9 was measured in addition to other related factors such as Bax, Bcl-2, caspase-9, and PARP-1.

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“…[ 23 ] Celecoxib reduces the risk of manifestation and growth of the various types of cancers, especially breast cancer. [ 24 ] Besides, pyrazoline motifs were reported as potent EGFR inhibitors 4 and 5 , [ 25,26 ] aurora kinase inhibitors, [ 27 ] telomerase inhibitors, [ 28 ] tubulin assembly inhibitors, [ 29 ] and so forth (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological evaluation, and in silico study of pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid derivatives

Rasal

Sonawane

Jagtap

2020

Archiv der Pharmazie

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A potential molecular hybridization strategy was used to develop 24 novel pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid and amide derivatives. The preliminary in vitro antimicrobial assay delivered four potential derivatives with growth inhibition in the range of 50.87–56.60% at the concentration of 32 µg/ml. In the search of an anticancer candidate, all derivatives were screened by NCI‐60 at 10 µM concentration, revealing that 12 derivatives were potential agents against the various types of cancer cell lines, with growth inhibition in the range of 50.21–108.37%. The in vitro cytotoxicity assay against the cell line HEK293 (human embryonic kidney cells) and the hemolysis assay of the representative potent compounds propose their potential for a good therapeutic index. In silico studies of the most potent derivatives qualified their significant pharmacokinetic properties with good predicted oral bioavailability and their adherence to Lipinski's rule of five for druglikeness. A molecular docking study against VEGFR‐2 with the best‐scored conformations reinforced their anticancer potency. The docking study of the most potent compound against VEGFR‐2 with the best‐scored conformations displayed a binding affinity (−9.5 kcal/mol) comparable with the drug sunitinib (−9.9 kcal/mol) and exhibited that tighter interactions at the active adenosine triphosphate site might be responsible for anticancer potency.

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Some 1,3,5-trisubstituted pyrazoline derivatives targeting breast cancer: Design, synthesis, cytotoxic activity, EGFR inhibition and molecular docking

Cited by 28 publications

References 22 publications

Chalcone Derivatives: Role in Anticancer Therapy

Chalcone Derivatives: Role in Anticancer Therapy

Synthesis, Antitumor Activities and Molecular Modelling of 4-Anilinoquinazoline Derivatives as EGFR-TK Inhibitors

Synthesis, biological evaluation, and in silico study of pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid derivatives

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