article · Molecules
Researchers have synthesised two new series of chemical hybrids combining isatin with thiazolidinone or thiazolo[3,2-a]benzimidazolone frameworks to target breast cancer. Laboratory testing evaluated the compounds against MCF-7 cells and the aggressive triple negative breast cancer line MDA-MB-231. Two specific molecules, designated 4m and 7b, demonstrated the strongest antiproliferative effects against MDA-MB-231 cells. Further investigation revealed that these compounds triggered programmed cell death, or apoptosis, marked by changes in Bax, Bcl-2, and caspase-3 protein levels. Compound 4m also prompted cell cycle arrest at the G2-M phase and led to a marked rise in apoptotic cell markers. Crucially, when tested against healthy breast and lung cell lines, both leading candidates exhibited notable tumour selectivity, and theoretical kinetic studies were conducted to profile their predicted absorption, distribution, metabolism, and excretion properties.
Triple negative breast cancer is notoriously difficult to treat and often requires new therapeutic candidates that selectively target tumour cells without excessive toxicity to healthy tissue. By identifying novel molecular structures that trigger programmed cell death and demonstrate selectivity over non-cancerous cells in preliminary tests, this research expands the chemical repertoire of potential lead structures for anti-cancer therapy development.
This work represents very early-stage drug discovery research that could inform the initial pipeline of pharmaceutical developers pursuing small-molecule breast cancer treatments. Practical application is distant, as the molecules have only been assessed in laboratory cell cultures alongside theoretical pharmacokinetic modelling. Substantial further optimisation, in vivo efficacy validation, and toxicity testing will be essential before commercial development or clinical translation can be realistically pursued.
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In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (<b>4a</b>⁻<b>n</b>) and thiazolo[3,2-<i>a</i>]benzimidazolone-isatin conjugates (<b>7a</b>⁻<b>d</b>), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds <b>4m</b> and <b>7b</b> emerged as the most active congeners against MDA-MB-231 cells (IC<sub>50</sub> = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds <b>4m</b> and <b>7b</b> were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid <b>4m</b> induced a fourfold increase in the percentage of cells at Sub-G₁, with concurrent arrest in G₂-M phase by 2.5-folds. Furthermore, hybrid <b>4m</b> resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates <b>4m</b> and <b>7b</b> displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.
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DOI: 10.3390/molecules23061420
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