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.

Induction of apoptosis of human gastric carcinoma SGC-7901 cell line by 5,7-dihydroxy-8-nitrochrysin in vitro

AIM： To investigate the effect of 5, 7-dihydroxy-8- nitrochrysin （NOChR） on apoptosis of human gastric carcinoma SGC-7901 cell line.METHODS： SGC-7901 cells were cultured in vitro and the inhibitory effect of NOChR on proliferation of SGC-7901 cells was measured by using an Ml-r assay. NOChR-induced apoptosis rate of SGC-7901 cells was detected using flow cytometry （FCM） with PI staining. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of NOChR on the proxisome proliferator-activated receptor-γ （PPARγ）, Bcl-2 and Bax protein expression of SGC-7901 cells was analyzed by Western blot.RESULTS： MIF assay showed that NOChR markedly inhibited proliferation of SGC-7901 cells in a dose- dependent manner, and when ICso was 4.14 μmol/L, the potency of NOChR was 10 times than that of lead compound, chrysin （ChR, IC50 was 40.56 μmol/L）, and was similar to 5-fluorouracil （5-FU, IC50 was 4.51 μmol/L）. FCM with propidium iodide （PI） staining demonstrated that the apoptosis rates of SGC-7901 cells treated with 1.25, 5.00 and 20.00 μmol/L NOChR for 48 h were 9.8% 4- 0.2%, 36.8% 4- 1.9% and 45.5% 4- 3.5%, respectively, and were significantly higher when treated with 5.00 and 20.00 μmol/L NOChR than that with 20.00 μmol/L ChR （12.9% 4- 1.5%）. DNA agarose gel electrophoresis showed that treatment of SGC-7901 cells with 20.00 μmol/L NOChR for 48 h resulted in typical DNA ladder bands of DNA of SGC-7901 cells, which could be eliminated by treating with 10.00 μmol/L GW9662, a blocker of PPARy. Western blot analysis revealed that after 24 h of treatment with 20.00 μmol/L NOChR, PPARgamma and Bax protein expression of SGC-7901 cells increased but Bcl-2 expression decreased; however, pre-incubation with 10.00 μmol/L GW9662 could efficiently antagonize and weaken the regulatory effect of 20.00 μmol/L NOChR on Bax and Bcl-2 protein expression of SGC-7901 cells. CONCLUSION： NOChR induces apoptosis of SGO7901 cell lines by activating PPARy and decreasing ratio of Bcl-2 to Bax.

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.