In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells p...In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.展开更多
Studies on the synthesis of antifungal and anticancer natural product,pseudolaric acid B,have led to the enantioselective synthesis of di-epi-trans-fused[5-7]-bicyclic co re skeleton.The synthesis was achieved in 10 l...Studies on the synthesis of antifungal and anticancer natural product,pseudolaric acid B,have led to the enantioselective synthesis of di-epi-trans-fused[5-7]-bicyclic co re skeleton.The synthesis was achieved in 10 linear steps,which features the Sharpless asymmetric epoxidation,cyanide-opening reaction of epoxide,and intramolecular[5+2]cycloaddition reaction as the key transformations.The stereochemistry was determined by the X-ray crystallographic analysis.展开更多
DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid...DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors.MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels,inducing hypomethylation of p16 and hyperacetylation of histones H_(3) K9 and H4 K8.Besides,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest.Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC.Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes.Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.展开更多
We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as...We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as PARP-1 inhibitors and antitumor activity,which are valuable for further research.In addition,the predicted ADME properties and proposed binding mode with PARP-1 of the compounds were obtained via computational simulation.展开更多
基金financial supports from the Shenzhen Development and Reform Committee(Nos.20151961 and 2019156)Department of Science and Technology of Guangdong Province(No.2017B030314083)。
文摘In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.
基金the financial support from the National Natural Science Foundation of China(Nos.21302078,21572089,21732001,21672017)the Program for Changjiang Scholars and the Innovative Research Team in Universities(PCSIRT:No.IRT_15R28)+3 种基金the State Key Basic Research Program of the PRC(No.2018YFC0310900)Shenzhen Science and Technology Innovation Committee(No.JCYJ20180504165454447)Shenzhen Basic Research Program(No.20180202)the National Ten Thousand Talent Program(the Leading Talent Tier)。
文摘Studies on the synthesis of antifungal and anticancer natural product,pseudolaric acid B,have led to the enantioselective synthesis of di-epi-trans-fused[5-7]-bicyclic co re skeleton.The synthesis was achieved in 10 linear steps,which features the Sharpless asymmetric epoxidation,cyanide-opening reaction of epoxide,and intramolecular[5+2]cycloaddition reaction as the key transformations.The stereochemistry was determined by the X-ray crystallographic analysis.
基金financial supports from China Postdoctoral Science Foundation (No.2018M631825)Shenzhen Development and Reform Committee (No.2019156)+2 种基金Shenzhen Science,Technology and Innovation Commission (No.JCYJ20180306174248782)Department of Science and Technology of Guangdong Province (No.2017B030314083)Shenzhen Bay Laboratory Open Funding (No.SZBL2019062801009)。
文摘DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors.MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels,inducing hypomethylation of p16 and hyperacetylation of histones H_(3) K9 and H4 K8.Besides,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest.Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC.Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes.Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.
基金Shenzhen Sci.& Tech.Bureau (Nos.JCYJ20170816170342439 and JCYJ20170413113448742) for the financial supports
文摘We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as PARP-1 inhibitors and antitumor activity,which are valuable for further research.In addition,the predicted ADME properties and proposed binding mode with PARP-1 of the compounds were obtained via computational simulation.