Design,Synthesis And Anti-tumor Activity Of Selective CDK4 Inhibitors With Template Of Tetrahydro-?-carboline

Fascaplysin is a nature product isolated from marine sponge of the ocean,which has attracted more attention due to its strong anti-tumor activity.It displays potent cytotoxicity against cancer cells by inducing cell apoptosis and angiogenesis,regulating metabolism,acting as a inhibitor of a cyclin-dependent kinase 4?CDK4?and others.However,it has reported that fascaplysin has limited potential as an anti-cancer drug due to its high toxicity.So it is imperative to develop the derivatives of fascaplysin with higher efficiency,selectivity and lower toxicity.Herein,three kinds of non-planar derivatives of tetrahydro-?-carboline�based fascaplysin have been designed and synthesized.Then anti-tumore activity test and computer simulation experiments were carried.25 title compounds of fascaplysin derivatives have been designed and synthesized,characterized by ¹H-NMR,¹³C-NMR,and ESI-MS.And compounds a2,a3,a7,b7were further characterized by X-ray diffraction methods,including the use of the Diamond software and Gussian software to perform crystal analysis and DFT calculations.The cytotoxicity were tested on the three cancer cell lines?HeLa,A549,Hep-G2?and one normal cell line WI38 by the MTT method,with fascaplysin as the positive control.The preliminary screening results indicated that compounds a and b presented good inhibition profile against Hela cells with the values of IC₅₀0 around 2.91�0.76?M for a7 and 4.71�0.70?M for b7.Moreover,the growth inhibitory to A549 cells was the most remarkable for the compound c4?12.44�1.35?M?.More importantly,the cytotoxicity to WI38 normal cells of the title compounds was much lower than that of fascaplysin.The results of cell cycle experiments showed that fascaplysin and compound a7 triggered cell cycle arrest at S phase and G₂ phase.Apoptosis cell experiment exhibited compound a7 induced apoptosis of A549 cells.The molecular docking studies and molecular dynamic simulation revealed that the title compounds could enter the receptor active cavity and interact with the key amino acid by hydrophobic action and hydrogen bond.The result of molecular dynamics simulation showed the presence of a stable trajectory.Thus,the results of this study shed light on the development of the hit compounds?a7,b7?as the novel and potential CDK4 inhibitor.