Abstract
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 (9a-f) or hippuric (11a,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 9b, 9e, and 9f 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 (SIs: 2 to >63 and 4-47, respectively). Compounds 9b, 9e, and 9f were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. In particular, 9e displayed promising antiproliferative (IC50 = 2.52 ± 0.39 μM), cell cycle disturbance, and pro-apoptotic actions in MDA-MB-231 cells.
Highlights
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 (9a−f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker
Pursuing our endeavor toward developing efficient inhibitors for the cancer-related isoform hCA IX,[16−20] here we present the design and synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic acid (9a−f) or hippuric acid (11a, b) moieties linked to 2-methylbenzofuran or 5bromobenzofuran tails via an ureido linker (Figure 1)
The obtained KI values pointed out that the main antitumor target isoform hCA IX was effectively inhibited by the here reported benzofuran-based derivatives decorated with benzoic acid moiety 9a−f with KI’s ranging between 0.56 and 5.1 μM, whereas hCA IX was moderately affected by the benzofuranbased carboxylic acids decorated with hippuric acid moiety (11a and 11b) with KI’s values equal to 35.7 and 19.0 μM, respectively
Summary
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 (9a−f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. Pursuing our endeavor toward developing efficient inhibitors for the cancer-related isoform hCA IX,[16−20] here we present the design and synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic acid (9a−f) or hippuric acid (11a, b) moieties linked to 2-methylbenzofuran or 5bromobenzofuran tails via an ureido linker (Figure 1).
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