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. 2019 May 20;20(10):2484.
doi: 10.3390/ijms20102484.

Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights

Mohamed A Abdelrahman  1 , Wagdy M Eldehna  2 , Alessio Nocentini  3   4 , Silvia Bua  5 , Sara T Al-Rashood  6 , Ghada S Hassan  7 , Alessandro Bonardi  8   9 , Abdulrahman A Almehizia  10 , Hamad M Alkahtani  11 , Amal Alharbi  12 , Paola Gratteri  13 , Claudiu T Supuran  14
Affiliations

Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights

Mohamed A Abdelrahman et al. Int J Mol Sci. .

Abstract

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 (KIs: 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 (KIs = 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 (IC50 = 4.89 ± 0.22 μM) than the reference drug Staurosporine (IC50 = 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.

Keywords: anticancer activity; diamide-based benzenesulfonamides; molecular docking; selective hCAIX inhibitors; synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of some reported benzenesulfonamides-based CAIs (I–IV) and the target compounds (5a–g and 5h).
Scheme 1
Scheme 1
Synthesis of diamide-based benzenesulfonamides 5a–h; Reagents and conditions: (i) Acetic anhydride/Hünig’s base/reflux 3 hrs., (ii) Glacial acetic acid/CH3COONa/reflux 4 h.
Figure 2
Figure 2
Percentage growth inhibition (GI%) for the target diamide-based benzenesulfonamides 5a–h towards the renal cancer UO-31 cell line.
Figure 3
Figure 3
Effect of diamide-based benzenesulfonamides 5a and 5h on the phases of cell cycle of UO-31 cells.
Figure 4
Figure 4
Effect of diamide-based benzenesulfonamides 5a and 5h on the percentage of annexin V-FITC-positive staining in UO-31 cells. The experiments were done in triplicates. The four quadrants identified as: LL, viable; LR, early apoptotic; UR, late apoptotic; UL, necrotic.
Figure 5
Figure 5
Docking of 5b (purple) and 5h (violet) in hCA II (A) and in hCA IX (B) active sites.
See this image and copyright information in PMC

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