Syntheses and evaluation of drug-like properties of CO-releasing molecules containing ruthenium and group 6 metal

Abstract

In this paper, drug-like properties of two series of carbonyl metal CO-releasing molecules, Ru(CO)3ClnL (n=1, L=amino acid or its derivatives 1–7, L=acetylacetone 8 or 2,2′-bipyridyl 9; n=2, L=aminopyridine derivatives 10–13; n=0, L=salicylaldehyde Schiff base 14–15) and M(CO)5L(M=Cr, Mo, W; L=glycine methyl ester 16–18; L=N-methyl imidazole 19–21), were preliminarily evaluated from four aspects involving in cytotoxicity, in vivo toxicity, bio-distribution and metabolism. Cytotoxic effects of all complexes were assayed by MTT. IC50 values of complexes 1–15 were 39.55–240.16mg/l, and those of complexes 16 and 18 were 21.36–22.21mg/l. Toxicity tests of mice used oral acute toxic class method and got LD50 values of some complexes; among them, LD50 of complex 1 was in 800–1000mg/kg, complex 7 in 1100–1500mg/kg and complex 18 in 75–125mg/kg. After several consecutive administrations, tested complexes severely damaged liver and kidney in both functional and morphological aspects. And by metal ions measurements using ICP-AES, we found that the tested complexes were unevenly distributed in tissues and organs. In vivo, RuII in complexes was oxidized to RuIII by P450 enzymes, and for Mo0 and W0 in complexes, part of them transformed into higher oxidation state, the others kept original state.