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

作者：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

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, 33(1): 1064-1073.

DOI：10.1080/14756366.2018.1482285

• Nitroimidazoles
• carbonic anhydrase IX
• zebrafish
• Xenopus oocytes
• in vivo inhibition

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 LD50 for both compounds was 3.5mM. Neither compound showed apparent toxicity below 300 mu M concentration. Above this concentration, both compounds altered the movement of zebrafish larvae. The IC50 was 0.14 +/- 0.02 mu M for DTP338 and 19.26 +/- 1.97 mu M 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.

• 出版日期2018-6-17