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

Research output

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)92-105
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume164
DOIs
Publication statusPublished - 15 Feb 2019

Fingerprint

Oxadiazoles
Carbonic Anhydrases
Sulfonamides
Protein Isoforms
Cells
Membranes
Carbonic Anhydrase I
Carbonic Anhydrase Inhibitors
Neoplasms
Molecular modeling
Carbonic Anhydrase II
Cytotoxicity
Cell Line
Structure-Activity Relationship
Pancreatic Neoplasms
Melanoma

Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

@article{8850bab558cd4e7e95b78ac303148cab,
title = "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",
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.",
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author = "Mikhail Krasavin and Anton Shetnev and Tatyana Sharonova and Sergey Baykov and Stanislav Kalinin and Alessio Nocentini and Vladimir Sharoyko and Giulio Poli and Tiziano Tuccinardi and Sofia Presnukhina and Tennikova, {Tatiana B.} and Supuran, {Claudiu T.}",
year = "2019",
month = "2",
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journal = "European Journal of Medicinal Chemistry",
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TY - JOUR

T1 - Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides

T2 - Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

AU - Krasavin, Mikhail

AU - Shetnev, Anton

AU - Sharonova, Tatyana

AU - Baykov, Sergey

AU - Kalinin, Stanislav

AU - Nocentini, Alessio

AU - Sharoyko, Vladimir

AU - Poli, Giulio

AU - Tuccinardi, Tiziano

AU - Presnukhina, Sofia

AU - Tennikova, Tatiana B.

AU - Supuran, Claudiu T.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - 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.

AB - 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.

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KW - Hypoxic environment

KW - Isoform-selective inhibitors

KW - Isosteric replacement

KW - Periphery groups

KW - Primary sulfonamides

KW - Subnanomolar inhibition

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