Design,synthesis,and biological evaluation of novel chrysin derivatives as poly(ADP-ribose)polymerase 1(PARP1)inhibitors for the treatment of breast cancer

In this study,we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly(ADP-ribose)polymerase 1(PARP1).Among these derivatives,compound 5d emerged as the most effective chrysin-based inhibitor of PARP1,with an IC50 value of 108 nmol·L^(-1).This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage.Furthermore,5d induced apoptosis and caused an extended G1/S-phase in these cell lines.Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1.In vivo,in a xenograft model,5d effectively reduced tumor growth by downregulating PARP1 expression.Overall,compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.

Synthesis and anti-tumor activities of novel 7-O-amino acids chrysinderivatives

Objective: To design and synthesize a series of chrysin derivatives and evaluate the antitumor activities with MTT assay, so as to investigate molecular structure-activity relationship with molecular docking.Methods: Target products were synthesized with high yield by substitution reaction, hydrolysis reaction,esterification reaction, and saponification reaction in sequence, and activities of all compounds were evaluated with human gastric carcinoma cell lines MGC-803 and human breast carcinoma cell lines MCF-7 through standard MTT assay. Molecular docking results were calculated with Surflex Geom X programme of Sybyl X-2.0 version workstation.Results: 7-O-amino acids chrysin derivatives 6 a–6 l were synthesized and their inhibitory effects were evaluated by comparing the material chrysin with positive control drug 5-fluorouracil(5-FU). Among these derivatives, compound 5 b(IC50= 24.50 ± 2.26 μmol/L), 5 k(IC50= 24.30 ± 2.19 μmol/L), and 6 f(IC50= 24.61 ± 2.01 μmol/L) showed better inhibitory activities against MGC-803 cell lines, and compound 5 g(IC50= 13.15 ± 1.73 μmol/L) and 5 j(IC50= 12.34 ± 1.25 μmol/L) showed better inhibitory activities against MCF-7 cell lines than chrysin and 5-FU. Molecular docking scores showed a credible consistency compared with MTT results.Conclusion: Compounds 5 b, 5 d, 5 g, 5 j, 5 k, and 6 f showed good antiproliferative effects on specific tumor cells, and compound 5 g should be researched further when according to molecular docking.