Syntheses and evaluation of drug-like properties of CO-releasing molecules containing ruthenium and group 6 metal.
In this paper, drug-like properties of two series of carbonyl metal CO-releasing molecules, Ru(CO)₃Cl(n)L (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 21.36-22.21 mg/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 800-1000 mg/kg, complex 7 in 1100-1500 mg/kg and complex 18 in 75-125 mg/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, Ru(II) in complexes was oxidized to Ru(III) by P450 enzymes, and for Mo(0) and W(0) in complexes, part of them transformed into higher oxidation state, the others kept original state.
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou, PR China.
Pengpeng
P
Wang
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou, PR China.
Huapeng
H
Liu
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou, PR China. Electronic address: zhaoqy@lzu.edu.cn.
Quanyi
Q
Zhao
The First Affiliated Hospital of Lanzhou University, Lanzhou, PR China.
Yonglin
Y
Chen
School of Stomatology of Lanzhou University, Lanzhou 730000, PR China.
Bin
B
Liu
School of Stomatology of Lanzhou University, Lanzhou 730000, PR China.
Baoping
B
Zhang
School of Stomatology of Lanzhou University, Lanzhou 730000, PR China.
Qian
Q
Zheng
D002248:Carbon Monoxide / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D012428:Ruthenium / Q000737:chemistry*; D014018:Tissue Distribution
D002248:Carbon Monoxide; D012428:Ruthenium
CO-releasing molecules; Distribution; Drug-like properties; Metabolism; Toxicity