Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action.

Abstract

A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.

• Authors: Eva Havránková, Jozef Csöllei, Daniela Vullo, Vladimír Garaj, Pavel Pazdera, Claudiu T Supuran
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 77 Pg. 25-37 (04 2018) ISSN: 1090-2120 [Electronic] United States
• PMID: 29324250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Amino Alcohols
• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Sulfonamides
• Triazines
• Piperazine
• Carbonic Anhydrase I
• Carbonic Anhydrase II
• CA9 protein, human
• Carbonic Anhydrase IX

Topics

• Amino Alcohols (chemistry, pharmacology)
• Antigens, Neoplasm (metabolism)
• Carbonic Anhydrase I (antagonists & inhibitors, metabolism)
• Carbonic Anhydrase II (antagonists & inhibitors, metabolism)
• Carbonic Anhydrase IX (antagonists & inhibitors, metabolism)
• Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Piperazine (chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfonamides (chemistry, pharmacology)
• Triazines (chemistry, pharmacology)