Synthesis, toxicities and cell proliferation inhibition of CO-releasing molecules containing cobalt

Abstract

A series of carbon monoxide-releasing molecules (CO-RMs) based on µ2-alkyne dicobalt(0)hexacarbonyl complex esters, Co2(CO)6HCC–CH2OCOR (R = 2-acetyloxybenzoic acid 1; R = 2-hydroxy-benzoic acid 2; R = 3-phenyl-2-propenoic acid 3; R = ibuprofen 4; R = naproxen 5; R = glycyrrhetinic acid 6; R = glycyrrhizic acid 7), were synthesized and characterized by spectroscopic methods. In addition, the crystal structures of complexes 2 and 6 were determined by X-ray diffraction. Cytotoxic effects of all the complexes were assayed by MTT analysis, and their IC50 values were determined as 36–125 µM. Toxicity tests on mice by the oral acute toxic class method gave LD50 values for complexes 1 and 5 in the range of 2500–5000 mg kg−1 and for complex 6 over 5000 mg kg−1. The alkyne substituents significantly affect the rate of CO release and cytotoxicity. The apoptotic effects on HeLa cells were consistent with their cytotoxicities. The cell apoptosis rates were dependent on complex doses, and cell apoptosis mainly occurred by “late apoptosis.” In addition, the complexes also blocked the cell cycle at the G2/M phase and led to the loss of the mitochondrial membrane potential.