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Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

ABSTRACT: A series of hitherto unknown sulfonamide-incorporated α-aminophosphonate derivatives were synthesized through the one-pot, two-step FeCl₃-catalyzed coupling of 4-aminobenzenesulfonamide with the appropriate benzaldehydes and diethyl phosphite. The new sulfonamides inhibition studies were performed on four carbonic anhydrase isoforms, i.e., the cytosolic human (h) hCA I and II (off-targets) as well as transmembrane cancer-related hCA IX and XII (targets). Among the synthesized compounds, derivative 23 resulted in the most selective compound against both cancer-associated isoforms over the off-target hCA I (hCA I/IX = 78; hCA I/XII = 458) and hCA II (hCA II/IX = 10; hCA II/XII = 56) and the binding mode of both enantiomers R and S was investigated in silico.

SUBMITTER: Sobati M

PROVIDER: S-EPMC10424312 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

Sobati Marjan M Abdoli Morteza M Bonardi Alessandro A Gratteri Paola P Supuran Claudiu T CT Žalubovskis Raivis R

ACS medicinal chemistry letters 20230801 8

A series of hitherto unknown sulfonamide-incorporated α-aminophosphonate derivatives were synthesized through the one-pot, two-step FeCl<sub>3</sub>-catalyzed coupling of 4-aminobenzenesulfonamide with the appropriate benzaldehydes and diethyl phosphite. The new sulfonamides inhibition studies were performed on four carbonic anhydrase isoforms, i.e., the cytosolic human (h) hCA I and II (off-targets) as well as transmembrane cancer-related hCA IX and XII (targets). Among the synthesized compound ...[more]

PMID: 37583824

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Project description:The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO2 hydrase assay, and the inhibition constants (Ki) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV-Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (Ki = 4.9 nM) and XII (Ki = 5.6 nM). Additionally, it efficiently chelated Fe2+, Fe3+, and Cu2+ and showed promising antiproliferative activity (GI50 4.5-10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents.

Dataset Information

Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

Publications

Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

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