Screening And Mechanism Study Of Antitumor Activity Of Marine Bromophenol Derivatives

Tumors are the second biggest threat to human health,and lung cancer is the cancer with highest incidence and mortality.Most of the drugs for lung cancer are targeted drugs,such as Gefitinib.Although anti-tumor drugs for lung cancer have made some progress,drug resistance is currently prevalent in marketed drugs,which limits the application of drugs.Therefore,finding specific targets has become the focus of anti-tumor drug development.The ocean is rich in biological resources,and some marine-derived natural products exhibit excellent biological activity.Among them,bromophenol compounds are unique compounds of marine origin,and have biological activities such as anti-oxidation,antibacterial and anti-tumor.Our team combined bromophenol with nitrogen-containing heterocycles into a series of bromophenol-fluorenone compounds.In vitro MTT screening revealed that this series of compounds has a significant inhibitory effect on tumor cell proliferation.Among them,the compound BOS-102significantly inhibited the proliferation and clonal formation of A549 cells,induced apoptosis and G0/G1 phase arrest in A549 cells.The mechanism study showed that BOS-102 can activate the mitochondrial apoptotic pathway mediated by reactive oxygen species.Further research revealed that BOS-102 deactivated the PI3K/Akt pathway and activated MAPK signaling pathways.The eukaryotic translation initiation factor 4E（eIF4E）plays a key role in regulating the initiation of eukaryotic translation.And eIF4E is at a critical node in the tumor signaling pathway,making eIF4E a hot target for anti-tumor drug development.The current research on targeting eIF4E mainly targets the following aspects:interference with eIF4E/4IF4G interaction;inhibition of PI3K/Akt/mTOR-4EBP1signaling pathway and inhibition of Ras/ERK/MNK-eIF4E signaling pathway.Based on the structural characteristics of the current eIF4E-targeted compounds,we combined with the bromophenol and the amino-thiazole to synthesize a series of compounds.Our study found that the compound EGPI-1 significantly inhibited tumor cell growth and targeted regulation of eIF4E.Duolink PLA and western blot results showed that compound EGPI-1 distrupt eIF4E/eIF4G interaction.Further studies revealed that EGPI-1 inhibitd eIF4E phosphorylation and inhibitd PI3K/Akt/mTOR signaling pathway.Flow cytometry analysis showed that EGPI-1 induced apoptosis and G0/G1 phase arrest of A549 cells;induced mitochondrial damage and decreased mitochondrial membrane potential.In vivo nude mice xenograft study demonstrated that EGPI-1 has antitumor activity in vivo and that EGPI-1 was safe in animal experiments.The above studies indicated that EGPI-1 has the potential to be developed into a novel anti-tumor drug.Ovarian cancer is a serious threat to women’s health and its mortality rate is higher than breast cancer.In recent years,with the successive listing of PARP inhibitors（olaparib,rucaparib,niraparib,talazoparib）,hopes have been given to patients with ovarian cancer.PARP is a DNA repair enzyme that plays a key role in the repair of cellular DNA single-strand damage.Inhibition of PARP（primarily PARP-1）can cause double-stranded damage to cells and can lead to death of BRCA-deficient cells.Based on the structural characteristics of the listed drugs,the research group combined a thiol group with a bromophenol group to synthesize a series of bromophenol-amino thiourea compounds.In vitro enzymatic activity demonstrated that four of the compounds selectively inhibited PARP-1 activity,with compound 11 having an IC₅₀ of 29.5 nM for PARP-1 and an IC₅₀ of>1000 nM for PARP-2.MTT assay showed that compound 11 significantly inhibited the proliferation of ovarian cancer cell SK-OV-3,induced apoptosis,ROS accumulation and G2/M phase arrest in SK-OV-3 cells.Further experiments showed that compound11 can induce DNA double-strand damage and H2AX phosphorylation,and inhibit PAR formation caused by H₂O₂.Proteomics studies showed that compound 11inhibits cellular DNA repair.In vivo nude mice xenograft experiments showed that compound 11 significantly inhibit the growth of xenografts in mice,and the mechanism study indicated that the antitumor activity of compound 11 in vivo was through inhibiting PARP-1.Animal experiments indicated that compound 11 was safe.The above experiments provide a powerful experimental basis for the development of selective PARP-1 inhibitors,and provide a theoretical basis for the study of new drugs for the treatment of ovarian cancer.