article · Drug Design Development and Therapy
Researchers designed and synthesised four series of isatin-benzoazine hybrid molecules combining isatin with quinazoline, phthalazine, or quinoxaline cores to evaluate their anticancer properties. Laboratory testing of these hybrids against human colon, breast, and lung cancer cell lines identified phthalazine-linked hybrids, designated 8b to 8d, as the most active antiproliferative agents. Compound 8c demonstrated notable efficacy in lung cancer cells by triggering apoptosis through a fivefold increase in caspase 3/7 enzyme activity. Cell cycle analyses showed that 8c increased the proportion of cells in the G1 phase while decreasing those in the S and G2/M phases. Furthermore, compound 8c displayed inhibitory activity against the multidrug-resistant NCI-H69AR lung cancer line, with a half-maximal inhibitory concentration of 9.5 micromolar. Its metabolic breakdown was also profiled in vitro using rat liver microsomes.
Multidrug resistance poses a major obstacle in treating lung and other cancers effectively. Developing hybrid molecules that unite two distinct bioactive components offers a way to trigger cancer cell death and circumvent existing resistance mechanisms. These early findings provide chemical leads that could inform future efforts to create new chemotherapeutic agents capable of treating difficult, resistant tumours.
This work is relevant to medicinal chemists and pharmaceutical developers seeking new small-molecule candidates for cancer therapies, specifically targeting drug-resistant lung cancers. Because the findings are derived entirely from in vitro cell and microsomal assays, the technology sits at an early discovery stage. Significant further preclinical work, including animal safety, pharmacokinetics, and in vivo efficacy testing, is necessary before commercial development could proceed.
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In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline (<b>6a-f</b> and <b>7a-e</b>)/phthalazine (<b>8a-f</b>)/quinoxaline (<b>9a-f</b>) hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids <b>8b-d</b> emerged as the most active antiproliferative congener in this study. Compound <b>8c</b> induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 µM against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid <b>8c</b> was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry.
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DOI: 10.2147/dddt.s140164
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