Design, Synthesis, and Anticancer Evaluation of Novel Indole Derivatives of Ursolic Acid as Potential Topoisomerase II Inhibitors. 2020

A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, Co-Innovation Center for Efficient Processing and Utilization of Forest Products, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China.

In this study, a series of new indole derivatives of ursolic acid bearing different N-(aminoalkyl)carboxamide side chains were designed, synthesized, and evaluated for their in vitro cytotoxic activities against two human hepatocarcinoma cell lines (SMMC-7721 and HepG2) and normal hepatocyte cell line (LO2) via MTT assay. Among them, compound 5f exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC50 values of 0.56 ± 0.08 μM and 0.91 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. A follow-up enzyme inhibition assay and molecular docking study indicated that compound 5f can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound 5f can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound 5f is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000097245 Ursolic Acid A pentacyclic triterpene that co-occurs with its isomer OLEANOLIC ACID in several plant species, and occurs in large amounts in FRUITS (such as CRANBERRIES; PEARS; PLUMS; and OLIVES), MEDICINAL HERBS, and other plants. (+)-Ursolic Acid,(3 beta)-3-Hydroxyurs-12-en-28-oic Acid,3-Epi-Ursolic Acid,3-Epiursolic Acid,3alpha-Ursolic Acid,3beta-Ursolic Acid,Olean-12-en-28-oic Acid, 3-Hydroxy-, Sodium Salt (1:1), (3beta)-,Sodium Oleanolate,Ursolic Acid Monosodium Salt,Ursolic Acid Sodium Salt,Ursolic Acid, (3beta)-Isomer, 2-(14)C-Labeled,Ursolic Acid, (3beta)-Isomer, Monopotassium Salt,Merotaine,3 Epi Ursolic Acid,3 Epiursolic Acid,3alpha Ursolic Acid,3beta Ursolic Acid,Oleanolate, Sodium
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014315 Triterpenes A class of terpenes (the general formula C30H48) formed by the condensation of six isoprene units, equivalent to three terpene units. Triterpene,Triterpenoid,Triterpenoids
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

Related Publications

A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
December 2017, Bioorganic chemistry,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
May 2015, European journal of medicinal chemistry,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
December 2015, Chemical biology & drug design,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
December 2023, Journal of enzyme inhibition and medicinal chemistry,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
February 2020, Bioorganic & medicinal chemistry letters,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
January 2012, European journal of medicinal chemistry,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
December 2020, Chemistry & biodiversity,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
January 2014, Bioorganic & medicinal chemistry,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
March 2006, Bioorganic & medicinal chemistry letters,
A-Liang Li, and Yun Hao, and Wen-Yan Wang, and Qing-Song Liu, and Yue Sun, and Wen Gu
September 2018, European journal of medicinal chemistry,
Copied contents to your clipboard!