Design, synthesis and biological evaluation of certain CDK2 inhibitors based on pyrazole and pyrazolo[1,5-a] pyrimidine scaffold with apoptotic activity

Ali, Ghada; Ibrahim, Diaa A.; Elmetwali, Amira M.; Ismail, Nasser S. M.

doi:10.1016/j.bioorg.2019.01.008

Cited by 46 publications

(33 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In medicinal chemistry, Knoevenagel products show pharmacological actions such as antiviral, antitubercular, anti-Parkinson's, anti-diabetic, anti-oxidant, and anti-cancer activity. The cytotoxic capacity of some Knoevenagel products is due to the inhibition of multiple enzyme targets and the induction of cellular events (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

The Knoevenagel reaction: a review of the unfinished treasure map to forming carbon–carbon bonds

Beurden

Koning

Molendijk

et al. 2020

Green Chemistry Letters and Reviews

113

View full text Add to dashboard Cite

The formation of carbon-carbon bonds is a quest that has required a lot of research throughout the last 125 years of history of chemistry. The creation of these bonds is key to producing a wide variety of advanced products with great societal importance. In the past, the Knoevenagel reaction entailed a big part of these reactions. All the Knoevenagel reactions are performed with nitrogen-based catalysts, categorized as tertiary amines, secondary amines, primary amines, and ammonium salts. These catalysts operate through different reaction paths, with very deviant intermediates concerning each category. Subsequently, these intermediates create new research opportunities considering their catalytic activity. Some remarks are made in the context of green chemistry, with quantitative analysis using e-factor calculations. In this perspective, the importance of Knoevenagel chemistry exemplified, which is repeatedly overlooked throughout history.

show abstract

Section: Introductionmentioning

confidence: 99%

The Knoevenagel reaction: a review of the unfinished treasure map to forming carbon–carbon bonds

Beurden

Koning

Molendijk

et al. 2020

Green Chemistry Letters and Reviews

113

View full text Add to dashboard Cite

show abstract

“…[15][16][17][18][19][20][21][22][23][24] Derivatives of pyridine scaffold also were widely used as both fungicides and anticancer drugs. 25) Based on these activities, the aim of this research was to design and synthesize new pyridine 2, pyrazoline 3, 4, pyrimidine 5, 6, thiazolone 7, 8a, 8b, 9 and triazepine 10 derivatives from thiophen-2-yl methylene thioxthiazolidine containing chalcone and evaluate their antimicrobial and anticancer activities maintaining the pharmacophoric essential features. Three dimensional quantitative structure activity relationship (3D QSAR) study was also performed to validate the observed pharmacological properties in order to investigate the most important parameter controlling their antitumor properties.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity

et al. 2021

View full text Add to dashboard Cite

“…The CDK2/cyclin A2 and c-Met protein kinase assays were performed using Kinase-Glo Plus luminescence kinase assay kit (Promega, Madison, WI, USA), as illustrated earlier [ 19 , 24 , 41 ]. In brief, the kinase activity was assessed by measuring the unreacted ATP remaining in solution after the kinase reaction.…”

Section: Methodsmentioning

confidence: 99%

“…AMBER99SB-ILDN force field was used for simulations [ 45 , 46 ]. As the force field does not contain parameters for the ligand, all ligands were parameterized using ANTECHAMBER to generate consistent parameters with the General Amber Force Field (GAFF) [ 41 ]. The AM1-BCC method was used to assign charges.…”

Section: Methodsmentioning

confidence: 99%

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

et al. 2021

View full text Add to dashboard Cite

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold (HI 5) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound. Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies. Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers (syn and anti) is responsible for binding affinity and intrinsic activity of HI 5. However, the molecular dynamic studies have confirmed that the syn-isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity. Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.

show abstract

Design, synthesis and biological evaluation of certain CDK2 inhibitors based on pyrazole and pyrazolo[1,5-a] pyrimidine scaffold with apoptotic activity

Cited by 46 publications

References 23 publications

The Knoevenagel reaction: a review of the unfinished treasure map to forming carbon–carbon bonds

The Knoevenagel reaction: a review of the unfinished treasure map to forming carbon–carbon bonds

Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

Contact Info

Product

Resources

About