article · Journal of Enzyme Inhibition and Medicinal Chemistry
Researchers synthesised a series of chemical compounds linking 2,4-thiazolidinedione with coumarin structures to assess their potential as selective enzyme inhibitors. Testing focused on human carbonic anhydrases IX and XII, which are linked to cancer, alongside widespread physiological forms known as carbonic anhydrases I and II. Specific molecules within the series, particularly compounds 10a, 10h, and 11a to 11c, demonstrated selective inhibition of carbonic anhydrases IX and XII in the sub-micromolar range without affecting the off-target enzymes I and II. These effective inhibitors were subsequently evaluated in laboratory antiproliferative tests. Among them, compound 11a proved to be the most potent inhibitor of cell growth and was analysed further for its effects on the cell cycle and programmed cell death in MCF-7 breast cancer cells.
Treating cancer effectively requires therapies that target tumour-specific mechanisms while leaving healthy tissues undamaged. Enzymes like carbonic anhydrases IX and XII are overactive in tumours but distinct from forms needed for normal bodily function. Developing selective compounds that shut down these cancer-linked enzymes without disturbing essential ones offers a pathway toward more targeted treatments with fewer unwanted side effects.
This research provides early-stage chemical leads for oncology drug discovery programmes targeting carbonic anhydrases IX and XII. The primary potential users are pharmaceutical and biotechnology developers working on targeted breast cancer therapies. Because the findings are derived entirely from preliminary biochemical and in vitro cell culture assays, these compounds remain at an early discovery stage, requiring extensive preclinical optimisation, safety profiling, and in vivo testing before any clinical translation.
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Different 2,4-thiazolidinedione-tethered coumarins <b>5a-b</b>, <b>10a-n</b> and <b>11a-d</b> were synthesised and evaluated for their inhibitory action against the cancer-associated <i>h</i>CAs IX and XII, as well as the physiologically dominant <i>h</i>CAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins <b>10a</b>, <b>10 h</b>, and 2-thienyl/furyl-bearing coumarins <b>11a-c</b> exhibited the best <i>h</i>CA IX (K<sub>I</sub>s between 0.48 and 0.93 µM) and <i>h</i>CA XII (K<sub>I</sub>s between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target <i>h</i>CA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins <b>10a</b>, <b>10 h</b> and <b>11a-c</b>, were assessed in an <i>in vitro</i> antiproliferative assay, and then the most potent antiproliferative agent <b>11a</b> was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.
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DOI: 10.1080/14756366.2021.2024528
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