Antiproliferative Activity, Multikinase Inhibition, Apoptosis- Inducing Effects and Molecular Docking of Novel Isatin–Purine Hybrids

The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.

• Publication year

  2023

• Venue

  Medicina

• Publication date

  2023-03-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.3390/medicina59030610PMID 36984611PMCID 10051310
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Design, Synthesis, and Biological Evaluation of 2-Mercaptobenzoxazole Derivatives as Potential Multi-Kinase Inhibitors

  2023cited by this paper
• New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis.

  2021cited by this paper
• Cancer statistics for the year 2020: An overview

  2021cited by this paper
• Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

  2021cited by this paper
• Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

  2021cited by this paper
• Synthesis, potential antitumor activity, cell cycle analysis, and multitarget mechanisms of novel hydrazones incorporating a 4-methylsulfonylbenzene scaffold: a molecular docking study

  2021cited by this paper
• A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

  2021cited by this paper
• New bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation.

  2021cited by this paper
• New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies

  2021cited by this paper
• Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

  2020cited by this paper
• Recent advances in isatin hybrids as potential anticancer agents

  2020cited by this paper
• Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities.

  2020cited by this paper
• Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors.

  2020cited by this paper
• Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis.

  2020cited by this paper
• Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies

  2019cited by this paper
• Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2.

  2019cited by this paper
• Design, synthesis and ability of non-gold complexed substituted purine derivatives to inhibit LPS-induced inflammatory response.

  2018cited by this paper
• Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold.

  2018cited by this paper
• Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

  2018cited by this paper
• Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma.

  2017cited by this paper
• Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers.

  2017cited by this paper
• Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

  2017cited by this paper
• Targeting the translation machinery in cancer

  2015cited by this paper
• Identification and Characterization of an Irreversible Inhibitor of CDK2

  2015cited by this paper
• Quantitation of VEGFR2 (vascular endothelial growth factor receptor) inhibitors--review of assay methodologies and perspectives.

  2015cited by this paper
• The history and future of targeting cyclin-dependent kinases in cancer therapy

  2015cited by this paper
• Clinical advances in the development of novel VEGFR2 inhibitors.

  2014cited by this paper
• Cell sensitivity assays: the MTT assay.

  2011cited by this paper
• Novel 6,8-dibromo-4(3H)quinazolinone derivatives of anti-bacterial and anti-fungal activities.

  2010cited by this paper
• Discovery of mitogen-activated protein kinase-interacting kinase 1 inhibitors by a comprehensive fragment-oriented virtual screening approach.

  2010cited by this paper
• The role of HER2 in cancer therapy and targeted drug delivery.

  2010cited by this paper
• The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications

  2007cited by this paper
• Analysis of apoptosis by propidium iodide staining and flow cytometry

  2006cited by this paper
• Targeting multidrug resistance in cancer

  2006cited by this paper
• Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.

  2005cited by this paper
• Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies.

  2000cited by this paper
• Growth factor signaling by receptor tyrosine kinases.

  1992cited by this paper
• The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.

  1988cited by this paper

• Design and Evaluation of New 6-Trifluoromethoxy-Isatin Derivatives as Potential CDK2 Inhibitors.

  2026cites this paper
• Study of di- (thiophene-2-yl)-1,2,4-triazine derivatives as multikinase inhibitors and anticancer agents

  2026cites this paper
• Characterization of soil-derived Bacillus subtilis metabolites against breast cancer: In vitro and in silico studies

  2025cites this paper
• In Silico and in vitro evaluation of the anticancer effect of a 1,5-Benzodiazepin-2-One derivative (3b) revealing potent dual inhibition of HER2 and HDAC1

  2025cites this paper
• Purine Scaffold in Agents for Cancer Treatment

  2025cites this paper
• An overview of isatin-derived CDK2 inhibitors in developing anticancer agents.

  2025cites this paper
• Synthesis and computational investigation of novel 2-mercaptoimidazolones as dual antimicrobial and anti-proliferative agents with potential multitargeting kinase inhibitory activity

  2025cites this paper
• A comprehensive review and recent advances on isatin-based compounds as a versatile framework for anticancer therapeutics (2020–2025)

  2025influential citation
• Multi-Kinase Inhibition by New Quinazoline–Isatin Hybrids: Design, Synthesis, Biological Evaluation and Mechanistic Studies

  2025cites this paper
• Recent advances in clinically approved nitrogenous heterocycle-based drugs and EGFR Tyrosine kinase inhibitors for precision oncology (2020–2024): a review

  2025cites this paper
• Structure-Driven Design and Precision Translation of Functionally Diverse Isatin-Based CDK2 Inhibitors: Advances in SAR, Polypharmacology, and Biomarker-Guided Cancer Therapy

  2025cites this paper
• Synthesis, cytotoxicity, apoptosis-inducing activity and molecular docking studies of novel isatin–podophyllotoxin hybrids

  2025cites this paper
• Exploring the potential of isatin hybrids as anticancer agents: recent advances and future prospective

  2025cites this paper
• Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids.

  2024cites this paper
• Discovery of 1H-benzo[d]imidazole-(halogenated)Benzylidenebenzohydrazide Hybrids as Potential Multi-Kinase Inhibitors

  2024influential citation
• Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets.

  2023cites this paper
• The design, synthesis, biological evaluation, and molecular docking of new 5‐aminosalicylamide‐4‐thiazolinone hybrids as anticancer agents

  2023cites this paper
• Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation

  2023cites this paper
• Novel pyrrolo[2,3-d]pyridine derivatives as multi-kinase inhibitors with VEGFR2 selectivity

  2023cites this paper
• Design, synthesis, antitumor evaluation, and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors

  2023cites this paper
• Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

  2023influential citation