Design Synthesis And Biological Evaluation Of Novel Coumarin-Based Hydroxamates As Potent Histone Deacetylase Inhibitors

Cancer is one of the deadliest diseases in the world.In China,the morbidity and lethal rate are second only to cardiovascular and cerebrovascular diseases.In addition to genetic factors,the occurrence of cancer also involves epigenetic modifications,including DNA methylation and demethylation,and covalent modification of histones.Epigenetic regulation is reversibly modified by corresponding enzymes,of which the most studied ones are histone deacetylase(HDAC)and histone acetylase(HAT),which coordinate with each other to jointly regulate the acetylation level of histone lysine residue.Various experimental results indicate that HDAC is closely related to the generation and development of cancer,and it is highly expressed in many tumor cells.Histone deacetylase inhibitors(HDACis)inhibit tumor development through various mechanisms,such as inhibiting tumor cell invasion and migration,inhibiting neovascularization,regulating gene expression,and promoting cell apoptosis.This also motivates us to continue to develop related HDACis anticancer drugs.Five anti-cancer drugs for this target have been approved for marketing,namely SAHA,PXD101,LBH589,FK228 and CS055,which are used to treat cutaneous T-cell lymphoma(CTCL),multiple myeloma(MM)or peripheral T-cell lymphoma(PTCL).Coumarins are a class of aromatic natural products with an oxygen-containing heterocycle and are widely exsistent in nature.They usually have simple structures and various biological effects such as anti-virus,hypoglycemic,anti-tumor,anti-inflammatory,and antibacterial.In this paper,a series of hydroxamic acid histone deacetylase inhibitors containing coumarin structure were designed and synthesized using SAHA as a template,a total of 38.Among them are 12 compounds of series A,which mainly explore the chain length of the Linker region,and finally determine n = 7 as the optimal number of carbon chains.Based on this,26 compounds of series B were further modified,mainly to modify the Cap region.Almost all the compounds showed enzyme inhibitory activity better than the control drug SAHA,and even individual compounds could reach 30-50 times of SAHA,and the activity was evaluated through various biological experiments.Such as enzyme activity,cell activity,Western blot,Cell cycle,Apoptosis,Molecular docking.Western blot experiments showed that the compound up-regulated the levels of acetylated histones H3 and H4 in a dose-dependent manner;scratch and cloning experiments showed that the compound exhibited certain anti-metastatic and anti-proliferative activities;cell cycle and apoptosis experiments showed that the compound could stall the cells in the G2/M phase and promote apoptosis.Finally,a molecular docking experiment briefly evaluated the ability of the compound to bind to HDAC1.In short,the introduction of coumarin structural fragment is necessary and feasible,and this series of compounds provide us with a solid foundation for exploring HDACis with high efficiency and low toxicity.