article · ACS Medicinal Chemistry Letters
New benzofuran-based carboxylic acid derivatives featuring benzoic or hippuric acid groups connected via an ureido linker were synthesised and evaluated for their ability to inhibit human carbonic anhydrase isoforms I, II, IX, and XII. Several compounds, specifically 9b, 9e, and 9f, acted as submicromolar inhibitors of the cancer-related hCA IX isoform with inhibition constants between 0.56 and 0.91 micromolar. These derivatives displayed selectivity for the target hCA IX enzyme over off-target isoforms hCA I and hCA II. When tested against MCF-7 and MDA-MB-231 human breast cancer cell lines, compounds 9b, 9e, and 9f exhibited antiproliferative effects. Compound 9e showed particular potency against MDA-MB-231 cells, generating an inhibitory concentration of 2.52 micromolar alongside cell cycle disturbance and pro-apoptotic effects.
Carbonic anhydrase IX is closely associated with tumour development, making it an attractive target for selective anticancer therapies. Creating small molecules that selectively target this isoform while sparing non-target enzymes helps minimise potential toxicity. These findings provide useful lead compounds showing concurrent enzyme inhibition and cancer cell antiproliferative activity for oncology researchers studying breast cancer mechanisms.
This work is at the early-stage discovery phase, producing candidate chemical leads that may interest oncology-focused biotechnology and pharmaceutical developers. The compounds could inform the design of targeted therapeutics directed at carbonic anhydrase IX in breast cancer. Substantial downstream research, including further in vitro profiling, in vivo efficacy testing, and pharmacological optimisation, is required before any commercial or clinical application is feasible.
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Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (<b>9a</b>-<b>f</b>) or hippuric (<b>11a,b</b>) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. The target carboxylic acids were evaluated for the potential inhibitory action against hCAs I, II, IX, and XII. Superiorly, benzofuran-containing carboxylic acid derivatives <b>9b</b>, <b>9e</b>, and <b>9f</b> acted as submicromolar hCA IX inhibitors with KIs = 0.91, 0.79, and 0.56 μM, respectively, with selective inhibitory profile against the target hCA IX over the off-target isoforms hCA I and II (<i>SI</i>s: 2 to >63 and 4-47, respectively). Compounds <b>9b</b>, <b>9e</b>, and <b>9f</b> were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. In particular, <b>9e</b> displayed promising antiproliferative (IC<sub>50</sub> = 2.52 ± 0.39 μM), cell cycle disturbance, and pro-apoptotic actions in MDA-MB-231 cells.
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DOI: 10.1021/acsmedchemlett.0c00094
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