Synthetic Strategies and Computational Inhibition Activity Study for Triazinyl-Substituted Benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Carbonic Anhydrases.

Mária Bodnár Mikulová,Dáša Kružlicová,Peter Mikuš,Claudiu T Supuran,Daniel Pecher

doi:10.3390/ijms21103661

Mária Bodnár Mikulová, Dáša Kružlicová + Show 3 more

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https://doi.org/10.3390/ijms21103661

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Abstract

Various sulfonamide derivatives are intensively studied as anticancer agents owing to their inhibitory activity against human tumor-associated carbonic anhydrase isoforms. In this work, different synthetic procedures for the series of 1,3,5-triazinyl-aminobenzenesulfonamide conjugates with amino acids, possessing polar uncharged, negatively charged, and hydrophobic side chain, were studied and optimized with respect to the yield/purity of the synthesis/product as well as the time of synthetic reaction. These procedures were compared to each other via characteristic HPLC-ESI-DAD/QTOF/MS analytical product profiles, and their benefits as well as limitations were discussed. For new sulfonamide derivatives, incorporating s-triazine with a symmetric pair of polar and some less-polar proteinogenic amino acids, inhibition constants (KIs) against four human carboanhydrases (hCAs), namely cytosolic hCA I, II, transmembrane hCA IV, and the tumor-associated, membrane-bound hCA IX isoforms, were computationally predicted applying various methods of the advanced statistical analysis. Quantitative structure-activity relationship (QSAR) analysis indicated an impressive KI ratio (hCA II/hCA IX) 139.1 and hCA IX inhibition constant very similar to acetazolamide (KI = 29.6 nM) for the sulfonamide derivative disubstituted with Gln. The derivatives disubstituted with Ser, Thr, and Ala showed even lower KIs (8.7, 13.1, and 8.4 nM, respectively).

Highlights

Human carbonic anhydrase IX is a zinc metalloenzyme with extracellular active site catalyzing reversible hydration of carbon dioxide to regulate the acid-base balance. human carboanhydrases (hCAs) IX differs from other hCA isozymes in several properties
Hypoxic tumor microenvironment is upregulated by hypoxia-inducible factor 1 (HIF) that activates a gene expression of mediators in various enzymatic pathways and angiogenesis such as glucose transporters, vascular endothelial growth factor as well as hCA IX [5,6]
The newly proposed water based synthetic strategies represent an attractive solution for the preparation of 1,3,5-triazinyl-substituted benzenesulfonamide derivatives containing a symmetric pair of the amino acids with various polarities

Summary

Introduction

Human carbonic anhydrase IX (hCA IX) is a zinc metalloenzyme with extracellular active site catalyzing reversible hydration of carbon dioxide to regulate the acid-base balance. hCA IX differs from other hCA isozymes in several properties. Human carbonic anhydrase IX (hCA IX) is a zinc metalloenzyme with extracellular active site catalyzing reversible hydration of carbon dioxide to regulate the acid-base balance. The main structural difference is a presence of the N-terminal proteoglycan-like (PG) domain in the extracellular protein part [1,2]. The PG domain plays a substantial role in adhesion, proliferation, and cell invasion under hypoxia and acidosis microenvironment conditions often contained in solid tumors [3,4]. Hypoxic tumor microenvironment is upregulated by hypoxia-inducible factor 1 (HIF) that activates a gene expression of mediators in various enzymatic pathways and angiogenesis such as glucose transporters, vascular endothelial growth factor as well as hCA IX [5,6]. HCA IX is only rarely expressed in normal tissues (such as the gastric mucosa, pancreas, and intestine) [18], it can be considered to be a highly selective tumor marker

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