article · Journal of Medicinal Chemistry
Dual-action therapeutics that target multiple pathways simultaneously offer a promising route for tackling cancer. Hypoxia-activatable genes, including carbonic anhydrase and vascular endothelial growth factor, contribute significantly to tumour growth and progression in low-oxygen environments. In response, a series of thirty novel sulfonamide molecules was designed and synthesised based on the known inhibitor SLC-0111. These compounds incorporated substituted 1,5-diaryl-1,2,4-triazoles in place of the standard tail group, alongside positional changes to the sulfamoyl group and alterations to the linker length. Biological evaluation against several carbonic anhydrase isoforms and a sixty-cell cancer screening panel identified leading compounds with dual inhibitory activity against carbonic anhydrase and vascular endothelial growth factor receptor 2. Further tests demonstrated selective activity against specific breast cancer cell lines over non-tumorigenic breast cells, supported by molecular docking that revealed how these molecules bind to their intended targets.
Hypoxic conditions inside tumours often drive aggressive cancer growth and therapy resistance. Developing a single molecule capable of simultaneously blocking tumour adaptation to low oxygen and tumour-driven blood vessel formation offers an efficient route to disrupt disease progression. This dual-action approach could support the discovery of targeted anti-cancer therapeutics that effectively suppress tumours while sparing healthy tissue.
This work represents early-stage laboratory research identifying small-molecule candidates for dual-target cancer therapies. The findings may interest oncology drug discovery teams and pharmaceutical developers working on hypoxic solid tumours, particularly breast cancer. Because testing has thus far been limited to cell line assays and molecular docking models, substantial further work, including in vivo efficacy, selectivity, and safety studies, is required before clinical development is possible.
AI-generated from the published abstract. Always read the original work before citing.
Presently, dual targeting by a single small molecule stands out as an effective cancer-fighting weapon. Carbonic anhydrase (CA) and vascular-endothelial growth factor (VEGF) are hypoxia-activatable genes that are implicated in tumorigenesis and progression of hypoxic tumors at different levels. Herein, we designed and synthesized 30 1,5-diaryl-1,2,4-triazole-tethered sulfonamides (<b>11a</b>-<b>f</b>, <b>12a</b>-<b>l</b>, <b>13a</b>-<b>f</b>, <b>15a</b>-<b>f</b>) as novel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitory activities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted 1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif position provided regioisomers <b>11a</b>-<b>f</b> and <b>12a</b>-<b>l</b>. Elongation of the ureido linker yielded derivatives <b>15a</b>-<b>f</b>. Inhibitory evaluations included a panel of <i>h</i>CAs (<i>h</i>CA I, II, IX, and XII) and screening against 60 cancer cell lines. Promising candidates were assessed for VEGFR-2 inhibition and selectivity and further evaluated on breast cancer cell lines (MCF-7 and T-47D) and the non-tumorigenic (MCF-10A) cells. Molecular docking studies explored the binding modes of the sulfonamides against <i>h</i>CA IX/XII and VEGFR-2 kinase.
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.1021/acs.jmedchem.3c00721
Is something wrong with this record? Report it or request removal.
Discussion
Have you built on this work, tried to replicate it, or seen it applied in practice? Share what you know. Verified researchers and MARATTO™ domain experts can open a discussion, and any member can reply. Contributions are reviewed before they appear.
No discussion yet. Open the first thread.
New to MARATTO™? Create a free account.
