Design,Synthesis,Anti-arrhythmic Activities Of Colchicine Derivatives

Arrhythmia is a serious threat to human health.There is an urgent need for new safe and effective antiarrhythmic drugs.In recent years,the research of tubulin inhibitor colchicine in the treatment of cardiovascular diseases has been paid more attention,but the side effects still limit its clinical application.Regarding colchicine as the lead compound,methoxy group of position 10 were selected to modify the structure of its parent nucleus.In order to retain the structure of colchicine nucleus,a new series of colchicine derivatives with fewer side effects were obtained through the introduction of different nitrogen containing side chains to preserve the survival of cardiovascular system disease.84 colchicine derivatives were synthesized by nucleophilic substitution reaction with colchicine as the starting material.The structures of all intermediates and target compounds were confirmed by nuclear magnetic resonance spectroscopy,carbon spectrum and mass spectrometry.HL02,RAW264.7 and rat cardiomyocytes cell lines were selected to test the inhibitory activity of target compounds.The results showed that the inhibitory activity of all the target compounds on the proliferation of the three cells was lower than that of the pilot compound colchicine,and the IC₅₀0 value of 12 target compounds increased by more than 30 times than colchicine.Using these 12 compounds as the preferred compounds,the potential of their application in cardiovascular system diseases was further evaluated in isolated rat cardiac contractile function test,CaCl₂ induced rat thoracic aorta vascular smooth muscle contraction inhibition test and[³H]ryanodine isotope binding experiment.The results showed that in the isolated rat cardiac systolic and contractile function experiments,4 preferred compounds 3-13,3-14,3-15,3-24showed negative heart rate or negative inotropic action under 30 nM concentration.It was worth further investigating its antiarrhythmic activity.Under the concentration of?M,the optimized compounds showed a contractile inhibitory effect on CaCl₂ induced aortic smooth muscle in rats.IC₅₀0 values of the tested compounds were 3-25 20.7?M,3-14 52.7?M,3-18 53.8?M,3-15 55.8?M,3-13 56.9?M,3-11 58.9?M,3-17 73?M,3-24 124.8?M,Colchicine 1.8mM.Compared with colchicine,the contractile inhibitory activity of vascular smooth muscle increased by 14-70 times.The[³H]ryanodine isotope binding assay showed that the preferred compound 3-15 and 3-25 were active in the heart-type ryanodine receptor,while the preferred compound 3-14 showed an inhibitory effect on the myocardial type ryanodine receptor.And compound 3-14 also has a certain regulatory effect on the skeletal muscle type ryanodine receptor,and its activity is significantly higher than that of the leading compound colchicine.To sum up,in this topic a series of preferred compounds were obtained by structural optimization,and their toxicity was significantly reduced compared with the lead compound colchicine.The potential of their application in the treatment of cardiovascular disease was verified by the experiment of isolated rat cardiac contractile and contractile function,rat thoracic aorta smooth muscle contraction inhibition test and[³H]ryanodine isotope binding experiment.4 of these compounds are worth further investigation of antiarrhythmic activity at the concentration of nM and provide a new lead compound for the development of a new type of safe and low toxic antiarrhythmic drugs.