Combining carbonic anhydrase and thioredoxin reductase inhibitory motifs within a single molecule dramatically increases its cytotoxicity

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 665 - 671
• Main Authors: Krasavin, Mikhail, Sharonova, Tatiana, Sharoyko, Vladimir, Zhukovsky, Daniil, Kalinin, Stanislav, Žalubovskis, Raivis, Tennikova, Tatiana, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cancer; cancer cell defence mechanisms; carbonic anhydrase inhibition; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; dual pharmacophores; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hypoxia; Isoforms; Life Sciences & Biomedicine; Michael acceptors; Molecular Structure; Oxidative stress; Pancreatic cancer; Pharmacology & Pharmacy; Rapid Communication; Science & Technology; Short Communication; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; synergistic effect; Thioredoxin; thioredoxin reductase inhibition; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Thioredoxin-Disulfide Reductase - metabolism; zinc-binding group; SYSTEM; hypoxia; DESIGN; Michael acceptors; PERIPHERY; cancer cell defence mechanisms; Anticancer agents; thioredoxin reductase inhibition; dual pharmacophores; zinc-binding group; carbonic anhydrase inhibition; oxidative stress; synergistic effect
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1734800

A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell's defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design.