The Structure Modification Of Resibufogenin And The Two Dimensional Evaluation Of Their Anti-tumor Activity And Cardiac Toxicity

Cardiac glycosides are steroid glycosides derived from existed in plants and animals with the function of enhancing myocardial systolic.It has been used to treat clinical heart diseases such as congestive heart failure and ventricular arrhythmia.In the late 1960s,it was reported that cardiac glycosides possessed anti-tumor activity with restraining cell proliferation in vitro and in vivo.The mechanism revealed in latest studies is that cardiac glycoside can bind to Na⁺/K⁺-ATPase,and this activated a series of signaling pathways in cells.After that,the signal can lead to cell apoptosis and cell phagocytosis,inhibite tumor cell proliferation,and weake the migration of tumor cells.However,these compounds have potential cardiac toxicities,which is an important factor in the failure of these compounds to be marketed successfully as antineoplastic agents.Hence,we put forward a two-dimensional evaluation strategy which combined anti-tumor activity with cardiac toxicity.The anti-tumor activity is tested with non-small cell lung cancer A549 cell line and cardiac toxicity is tested with normal fibroblasts GM08399 and myocardial cells of human induced pluripotent stem cells?hiPSC-CM?in vitro.Ultimately the therapeutic windows of the compounds were obtained based on the anti-tumor activity and cardiac toxicity..According to thought and design of the subject,we synthesized lead compound resibufogenin-14,15-ene,and then converted the beta-OH of C-3 in lead compound into ketone alpha-OH,oxime,ester and carbamate.However,the derivatives above did not have activitiesin the preliminary bioactive test,the C-3 bits of resibufogenin were converted into carbamates without any change of C-14,15-bit epoxy and C-3 beta-OH.In this paper,a total of 25 resibufogenin derivatives were prepared.Based on the preliminary activity tests in vitro and the two-dimensional evaluations of activity and toxicity,we found that the anti-tumor activities IC₅₀?A549?of some carbamate derivatives were 1.83-12.68times higher than resibufogenin,and the treatment window IC₅₀?GM08399?/IC₅₀?A549?of them increased by 1.73-6.90 times,IC₅₀?hiSPC-CM?/IC₅₀?A549?of them increased by 3.58-7.24 times.Among them,the IC50?A549?of derivatives 26 and 27 increased by 12.11 and12.68 times respectively,and the treatment window IC₅₀?hiSPC-CM?/IC₅₀?A549?of the two derivatives increased by 7.24 and 6.41 times respectively,and they showed good prospects for further study.