article · Archiv der Pharmazie
A series of 14 novel hydrazone-isatin derivatives were synthesised and evaluated for their antiproliferative activity against the NCI-60 cancer cell line panel. Among these candidates, compound VIIIb demonstrated notable inhibition of the epidermal growth factor receptor (EGFR). Computational assessments, including molecular docking, molecular dynamics, and binding free energy calculations, corroborated this enzymatic inhibition. Further profiling revealed that compound VIIIb possesses favourable drug-likeness properties. Cellular investigations showed that the compound decreased the proportion of cells in the G2/M phase and induced both early and late apoptosis at levels comparable to the clinical drug erlotinib. Molecular analysis confirmed this pro-apoptotic mechanism, showing that compound VIIIb elevated the expression of caspase-3 and Bax while suppressing Bcl-2 levels, supporting its profile as an anticancer lead.
Epidermal growth factor receptor (EGFR) is a central therapeutic target in multiple cancers. Identifying new molecules that inhibit this target while effectively inducing programmed cell death offers fresh avenues for oncology drug discovery. Because compound VIIIb achieves apoptotic activity comparable to an established clinical inhibitor in laboratory models, it presents a valuable chemical template for designing more effective targeted cancer therapies.
This work is at an early discovery stage, providing a candidate small molecule for medicinal chemistry teams and pharmaceutical developers working on oncology pipelines. While compound VIIIb demonstrates suitable drug-likeness and targeted in vitro activity, extensive progression is still required. Moving towards commercialisation will depend on subsequent in vivo pharmacokinetic profiling, safety studies, and preclinical efficacy testing before any clinical trials can be pursued.
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Merging isatin and arylhydrazone moieties constitutes an efficient strategy to access new potential anticancer derivatives. Consequently, 14 hydrazone-isatin derivatives were synthesized and evaluated for their antiproliferative activity against the NCI-60 cancer cell line panel. A kinase assay demonstrated that compound VIIIb inhibited the epidermal growth factor receptor (EGFR), which was confirmed by docking studies, molecular dynamics, and binding free energy calculations. Further characterizations showed that this compound possesses drug-likeness properties, showed a significant decrease of the cell population in the G2/M phase and led to a significant increase in early and late apoptosis, comparable to erlotinib. Also, VIIIb increased the expression of caspase-3 and Bax and decreased the expression of Bcl-2, confirming its potential as a new proapoptotic compound.
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DOI: 10.1002/ardp.202300244
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