Antitumor Activity And Mechanism Of Matrine Derivatives Based On Target Of Hsp90

Matrine is an alkaloid obtained from plants such as Radix Sophorae Flavescentis and Sophora Subprostrate by means of extraction and isolation.An increasing number of studies have shown that matrine have a wide range of pharmacological activities,such as anti-inflammatory,antibacterial,antiviral and antitumor effects,and some preparations have been applied in clinical use.However,due to its chemical structure,matrine has low bioavailability in vivo,unsuitable lipid-water partition coefficient,and large toxic side effects,resulting in some limitations in formulation development.Therefore,through chemical modification of the parent nucleus of matrine,the research group obtained a series of derivatives with new structures to solve the problems it faced.In this study,the anti-tumor activity of the newly synthesized compounds was investigated using cellular assay techniques,molecular biology techniques and tumor-bearing nude mice.In this paper,25 target compounds were screened for their effects on the viability of non-small cell lung cancer A549 cells,colon cancer HCT-116 cells,cervical cancer He La cells and liver cancer Bel-7402 cells,among which compound C4 showed the strongest antitumor effect.C4 also showed significant inhibition of tumor cell clonogenesis,migration,and invasion,in addition to exerting antitumor effects by affecting cell cycle distribution and regulating the activation of the mitochondrial apoptotic pathway.The study confirmed that the anilinothiazole structure of C4 could be inserted into the pocket of the N-terminal domain ATP binding site of heat shock proteins90 and enhanced the affinity by interacting with amino acid residues through a hydrogen bonding network,and the thermal shift assay demonstrated that its binding to the target protein was similar to that of the positive control drug.Finally,it was confirmed that C4 exerted anti-tumor effects by inhibiting PI3K/Akt signaling pathway,and showed some anti-tumor effects in nude mice compared with positive control group(P<0.01).