Toxicity, bio-distribution and metabolism of CO-releasing molecules based on cobalt

Abstract

CO-releasing molecules (CORMs) containing [Co2(CO)6] moiety show many bioactivities, such as anti-inflammatory and antitumor cell proliferation. However, so far, no one knows their properties in vivo. So, here, we evaluated some these kind CORMs from drug-like properties including cytotoxicity, toxicity in vivo, distribution and metabolism. The results show all the tested complexes displayed antiproliferative activity to HeLa cell and HepG2 cell lines, and their IC50 values were 36-110µM against HeLa cells and 39-140µM against HepG2 cells. Toxicity tests of mice, we used oral acute toxic class method and got their LD50 values; among them, LD50 of complex 1 and complex 4 were in 2500-5000mgkg(-1) and complex 7 over 5000mgkg(-1). The developmental toxicities of the complexes were investigated in embryonic zebrafish. The mortality, hatch rate, malformation, heart rate, spontaneous movement, and larval behavior were examined, and we found both complexes 4 and 7 have not toxicity at low concentration (<1.0μM) but have higher toxicity at high concentration (>5.0μM). After several consecutive i.p administrations, tested complexes severely damaged rat liver and kidney in both functional and morphological aspects. Through metal ion measurement using ICP-AES, we found the tested complexes were unevenly distributed in tissues and organs; complex 4 has a big prone to collect in liver, whereas complex 7 easily enters to kidney. After administration 480min later, most of complex 7 excreted from kidney and entered urine, while complex 4 needed 9h at least. This results show cobalt did not accumulate, and could excrete with the urine. In vivo, Co(0) in complexes was oxidised to Co(II). In addition, the substituents significantly affected the rate of CO-release, cytotoxicity and their bio-distribution. In the view of these aspects, the CORMs based cobalt has a potential property to be a medicine.

Keywords: CO-releasing molecule; Carbonyl metal; Cobalt; Distribution; Toxicity.