Design, Synthesis And Antitumor Activity Of Silybin Analog

Innovative research on natural products is one of the main directions of drug development today.In recent years,highly effective and low-toxic drugs extracted from natural plants have been widely used in clinical practice,and natural products and their analogues are an important source of new drug candidates.The natural product silybin comes from the plant silymarin,which is the main active ingredient of silymarin.Silybin is composed of two non-enantiomers of silybin A and silybin B,of which the average content of total flavonoids is about 50%,with a variety of pharmacological effects such as liver protection,anti-inflammatory,antioxidant,hypoglycemic and immunomodulatory,and studies have shown that silybin has a good inhibitory effect at all stages of tumor formation.Among the global anti-tumor drugs,protein kinase inhibitors are the majority,followed by monoclonal antibodies,apoptosis inhibitors,anti-inflammatory anti-cancer drugs,and angiogenesis inhibitors.Targets of antineoplastic drugs include cyclin-dependent kinases,topoisomerases,DNA polymerases,B lymphocyte antigen CD20,Erbb2 tyrosine kinases,epidermal growth factor,VEGF-2receptors,etc.Cyclin-dependent kinase 4/6(CDK4/6)is a popular anti-tumor target.In this paper,taking silybin as the mother,the structural transformation of its C-7 bit was carried out by using the principle of pharmacodynamic group splicing,and a series of silybin structural analogues were designed and synthesized.Firstly,the 5 hydroxyl groups of silybin were fully esterified for protection,then the C-7 phenol ester was selectively ammonialyzed,and finally sulfonylation was carried out,and a sulfonyl group was introduced at the C-7 position,and the corresponding amine was reacted to form a sulfonamide.And by recrystallization purification,reduce the reaction post-treatment,improve product purity and yield.The synthesized compounds have not been reported,and the compound structure has been confirmed by MS,1H-NMR and other methods.Computer-aided drug design technology was used to simulate the molecular docking of the CDK4/6 inhibitor Palbociclib with the target protein(PBD number: 5L2S),to resolve the key amino acid residue fragments of the target protein to play an active role,and to determine the active group that can bind to the key site.The results showed that Palbociclib was combined with amino acid residues of the CDK target protein by hydrogen bonds,hydrophobic bonds and van der Waals forces,and its amino linkage arm was combined with ALA286,the key amino acid residue of the CDK4/6 target protein.The cytotoxic activity of the compound was determined by MTT method,and the tumor cells were selected as human hepatocellular carcinoma cells(Hep G-2)with the CDK4/6 inhibitor Palbociclib as the positive control.Experiments show that the inhibition rate of Compound I1 on Hep G-2 is 59.67%,which is better than the positive control drug Palbociclib and has good anti-tumor activity.This paper provides a basis for further structural modification of silybin,compound I1 as a potential small molecule inhibitor of CDK4/6,which deserves further study.