基于DNA相互作用的17-芳香席夫碱取代的孕甾衍生物合成及抗肿瘤活性OA

The investigation of steroid-DNA interaction is very important for designing an improved therapeutic agent.In this work,five novel 17-aromatic schiff base-substituted pregnan derivatives(1-5)were synthesized,and the antiproliferative activity in vitro and interaction with calf thymus DNA(ct-DNA)were studied.The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide(MTT)assay showed that compounds 1 and 2 had better antitumor activity than other compounds against some carcinoma cell lines,and exhibited less cytotoxicity on normal human cells.In particular,the IC50 values of compounds 1 and 2 were(4.72±0.09)and(1.17±0.01)μmol/L against human ovarian carcinoma(SKOV3)cell line.Furthermore,fluorescence spectroscopy experimental results showed that compounds 1 and 2 bound to DNA preferentially through hydrophobic and π-π stacking interactions with binding constant(Kb)of 9.10×104 L/mol and 1.06×105 L/mol,respectively,indicating the higher binding affinity of compound 2 towards DNA.The ethidium bromide(EB)and Hoechst 33258 competitive binding experiments showed that intercalation should be the major binding mode of compounds 1 and 2 with DNA.The binding mode was further supported by circular dichroism spectrum analysis,viscosity measurements and molecular docking.The results of this work provided references for design and development of steroid antitumor drugs.