article · International Journal of Molecular Sciences
This research describes the synthesis and biological evaluation of a new series of diamide-based benzenesulfonamides (5a-h) as inhibitors of carbonic anhydrase (CA) isoforms. The study found that the tumour-associated isoforms hCA IX and XII were most effectively inhibited by these compounds. Notably, compounds 5a and 5h acted as potent hCA IX inhibitors, achieving single-digit nanomolar inhibition. Compound 5h demonstrated the best selectivity for hCA IX over hCA I and II, a finding supported by molecular docking simulations. Furthermore, compounds 5a, 5b, and 5h were tested for their antitumor activity against renal cancer UO-31 cells. Compound 5h proved to be the most potent, showing enhanced activity compared to the reference drug Staurosporine, and both 5a and 5h were shown to induce apoptosis in these cancer cells.
This research identifies new chemical compounds with potential for developing targeted cancer therapies. By selectively inhibiting specific enzymes involved in tumour growth and inducing cancer cell death, these findings contribute to the ongoing search for more effective and less toxic anticancer drugs.
This early-stage research identifies novel compounds with potent and selective inhibitory activity against carbonic anhydrase IX, an enzyme linked to tumour growth. These findings could inform the development of new anticancer drug candidates. Pharmaceutical companies and drug discovery programmes might utilise these compounds as leads for further optimisation and preclinical testing, aiming for future therapeutic applications in oncology.
AI-generated from the published abstract. Always read the original work before citing.
In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a-h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (<i>K</i><sub>I</sub>s: 8.3-123.3 and 9.8-134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (<i>K</i><sub>I</sub>s = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a-g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC<sub>50</sub> = 4.89 ± 0.22 μM) than the reference drug Staurosporine (IC<sub>50</sub> = 7.25 ± 0.43 μM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.3390/ijms20102484
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.
