New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity

Abstract

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides' cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC₅₀ = 8.39-16.90 μM against HepG-2 and 19.57-21.15 μM against MCF-7) comparing with doxorubicin (IC₅₀ = 13.76 ± 0.45, 17.44 ± 0.46 μM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC₅₀ = 1.33, 0.38 μM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC₅₀ = 0.43 μM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

Keywords: 1,2,3-Triazole; Antiproliferative; Carbonic anhydrase; Copper; Sulfonamide-based; VEGFR-2.

Figure 1

Cytotoxic agents with different mechanistic approaches that include benzenesulfonamide, 1,2,3-triazole, and/or glycoside scaffolds.

Figure 2

Design route of benzenesulfonamide-based targets bearing azido group in 3, 4 or 1,2,3-triazole-glycoside scaffolds in 6–13 targeting VEGFR-2 and Carbonic anhydrase inhibition.

Scheme 1

Synthesis of 1,2,3-triazolyl hybrid glycosides.

Figure 3

Preliminary cytotoxic evaluation of sulfonamide-based targets 3, 4, 6–13 through the MTT assay against human cancerous A-549, HepG-2, MCF-7, HCT-116 cell lines at 100 µM comparing with doxorubicin.

Figure 4

SAR study of sulfonamide-based derivatives 3, 4, 6–13 as cytotoxic agents against human cancer A-549, HepG-2, MCF-7, HCT-116 cell lines.

Figure 5

Examination of cell cycle and influence of benzenesulfonamide-1,2,3-triazole-glycoside 9 on the percentage of V-FITC-positive annexin staining in MCF-7 cells regarding to control.

Figure 6

Examination of cell cycle with benzenesulfonamide-1,2,3-triazole-glycoside 9.

Figure 7

Influence of benzenesulfonamide-1,2,3-triazole-glycoside 9 on apoptotic activity.

Figure 8

(A) & (B) views illustrated (2D and 3D) binding features of the benzenesulfonamide 1,2,3-triazole glycosides 7 and 9 within the active site of VEGFR 2 (PDB code: 4ASD), respectively.

Figure 9

(A) & (B) views illustrated (2D and 3D) binding features of the benzenesulfonamide 1,2,3-triazole glycosides 7 and 9 within the active site of hCA IX (PDB code: 3IAI), respectively.

Figure 10

(A) & (B) views illustrated (2D and 3D) binding features of the benzenesulfonamide-1,2,3-triazole-glycosides 7 and 9 within the active site of hCA XII (PDB code: 1JD0), respectively.