Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

Mikhail Krasavin; Anton Shetnev; Tatyana Sharonova; Sergey Baykov; Stanislav Kalinin; Alessio Nocentini; Vladimir Sharoyko; Giulio Poli; Tiziano Tuccinardi; Sofia Presnukhina; Tatiana B Tennikova; Claudiu T Supuran

doi:10.1016/j.ejmech.2018.12.049

Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

Eur J Med Chem. 2019 Feb 15:164:92-105. doi: 10.1016/j.ejmech.2018.12.049. Epub 2018 Dec 21.

Affiliations

¹ Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.
² The Ushinsky Yaroslavl State Pedagogical University, Yaroslavl, 150000, Russian Federation.
³ Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
⁴ Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.
⁵ Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
⁶ Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 30594030
DOI: 10.1016/j.ejmech.2018.12.049

Abstract

An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.

Keywords: 1,2,4-Oxadiazole; Cancer cells; Carbonic anhydrase; Hypoxic environment; Isoform-selective inhibitors; Isosteric replacement; Periphery groups; Primary sulfonamides; Subnanomolar inhibition.

MeSH terms

Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrases / drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery
Humans
Hypoxia
Melanoma / drug therapy
Melanoma / pathology
Neoplasms / drug therapy*
Neoplasms / pathology
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / pathology
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Oxadiazoles
Sulfonamides
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII