Syntheses, properties and bio-activities of water-soluble CO-releasing molecule based on manganese

Abstract

A series of water-soluble CO-releasing molecules, [Mn(CO)3NH2CHRCO2]2 (1-3), [M(CO)3Br[(Py-C = N)(Gly) n CO2] (M = Mn, Re, 4-7), Mn(CO)4[S2CNC m H n CO2] (8-12), were synthesized and characterized by (1)H NMR, IR and ESI-HRMS. The stability of all the complexes in solution was evaluated by means of UV, IR and (1)H NMR. Among all the complexes, complex 4 and complex 8 were stable in H2O, acidic aqueous solution and basic media; complex 1 was stable in acidic aqueous solution and weak basic media (pH < 9.4). The assays showed that each complex has CO-release ability; excess sodium dithionite can enhance CO release. Among them, complexes 8-12 were fast CO-releasers. In the test of the cell proliferation, all the complexes showed anti-proliferative activities for HeLa and HepG2. In particular, complex 8 displayed a 3.5-fold anti-proliferative activity on HeLa cells (IC50 23.13 μM) and fivefold on HepG2 cells (34.00 μM) compared with 5-FU. What is more, the complexes distinctly influenced cell cycle and promoted cell apoptosis; complex 1 arrested HeLa cells in S phase, whereas complex 4 and complex 8 arrested in G2/M phase; all the complexes induced HeLa cells "Early apoptosis". In addition, all complexes 1, 4 and 8 decreased intracellular nitrite levels, and complex 8 was stronger than both of the others. All these data demonstrate that complex 8 has potential to be a drug candidate. Three different categories of water-soluble CORMs 1-12 were synthesized, and their stability were evaluated. The biological activities were preliminarily evaluated. This includes anti-proliferation and anti-inflammatory properties.

Keywords: Anti-inflammatory; CO-releasing molecule; Manganese; Toxicity.