4.7 Article

Development of 4-((3-oxo-3-phenylpropyl)amino)benzenesulfonamide derivatives utilizing tail/dual-tail approaches as novel carbonic anhydrase inhibitors

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114412

关键词

Carbonic anhydrase inhibitors; Dual-tail approach; Benzenesulfonamide; SLC-0111 analogues; Hypoxic tumors

资金

  1. King Saud University, Riyadh, Saudi Arabia [RSP-2021/103]
  2. Italian Ministry for Education and Science (MIUR) [2017XYBP2R]
  3. Ente Cassa di Risparmio di Firenze (ECRF) [CRF2020.1395]

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In this study, tail/dual tail approaches were used to design and synthesize benzenesulfonamide derivatives as new SLC-0111 analogs with carbonic anhydrase (CA) inhibitory activity. The results showed that these derivatives had varying effects on different CA isoforms. Appending a second hydrophilic tail significantly enhanced the inhibitory activities towards hCA IX and hCA XII isoforms. SAR analysis revealed the importance of grafting the sulfamoyl functionality at para-position and incorporating a bulky hydrophobic tail for CA inhibitory activity. The most potent hCA IX inhibitors exhibited strong cell growth inhibitory activity against breast cancer cell lines.
In the current work, we adopted the tail/dual tail approaches to design and synthesize the benzenesulfonamide derivatives 6a-b, 8, 10a-b, 12a-b, 14, and 16 as new SLC-0111 analogs endowed with carbonic anhydrase (CA) inhibitory activity. All the prepared benzenesulfonamide derivatives were tested for their inhibitory action to-wards hCA isoforms; hCA I, II, IX, and XII. The results revealed their ability to affect the examined isoforms in variable degrees with K-I ranges: 49.3-6459 nM for CA I, 5.1-4171 nM for CA II, 9.4-945.1 nM for CA IX, and 5.2-1159 nM for CA XII. As expected, appending a second hydrophilic tail (ethanolamine) in compound 16 significantly enhanced the inhibitory activities towards hCA IX and hCA XII isoforms by about 5-fold in comparison to its single tail analogue 6c (K-I = 51.5 and 28.2 nM for 6c vs. 10.2 and 5.2 nM for 16, respectively). Moreover, SAR analysis pointed out the significance of grafting the sulfamoyl functionality at para-position, as well as the incorporation of a bulky hydrophobic tail for CA inhibitory activity. The most potent hCA IX inhibitors (6f and 16) displayed efficient cell growth inhibitory activity against breast cancer cell lines; T-47D (IC50 = 19 and 10.9 mu M, respectively) and MCF-7 (IC50 = 7.5 and 5.7 mu M, respectively).

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