Nitroimidazole-based inhibitors DTP338 and DTP348 are safe for zebrafish embryos and efficiently inhibit the activity of human CA IX in Xenopus oocytes

• Published in: Journal of enzyme inhibition and medicinal chemistry 2018-01, Vol.33 (1), p.1064-1073
• Main Authors: Aspatwar, Ashok, Becker, Holger M., Parvathaneni, Nanda Kumar, Hammaren, Milka, Svorjova, Aleksandra, Barker, Harlan, Supuran, Claudiu T., Dubois, Ludwig, Lambin, Philippe, Parikka, Mataleena, Parkkila, Seppo, Winum, Jean-Yves
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; carbonic anhydrase IX; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Chemical Sciences; Dose-Response Relationship, Drug; Humans; in vivo inhibition; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium marinum - drug effects; Nitroimidazoles; Nitroimidazoles - chemical synthesis; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacology; Oocytes - drug effects; Oocytes - metabolism; Research Paper; Structure-Activity Relationship; Xenopus; Xenopus oocytes; zebrafish; Zebrafish - embryology
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2018.1482285

Carbonic anhydrase (CA) IX is a hypoxia inducible enzyme that is highly expressed in solid tumours. Therefore, it has been considered as an anticancer target using specific chemical inhibitors. The nitroimidazoles DTP338 and DTP348 have been shown to inhibit CA IX in nanomolar range in vitro and reduce extracellular acidification in hypoxia, and impair tumour growth. We screened these compounds for toxicity using zebrafish embryos and measured their in vivo effects on human CA IX in Xenopus oocytes. In the toxicity screening, the LD 50 for both compounds was 3.5 mM. Neither compound showed apparent toxicity below 300 µM concentration. Above this concentration, both compounds altered the movement of zebrafish larvae. The IC 50 was 0.14 ± 0.02 µM for DTP338 and 19.26 ± 1.97 µM for DTP348, suggesting that these compounds efficiently inhibit CA IX in vivo. Our results suggest that these compounds can be developed as drugs for cancer therapy.