Discovery of highly potent tubulin polymerization inhibitors: Design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines. 2021

Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.

By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
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
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
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
D014404 Tubulin A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from SPERM FLAGELLUM; CILIA; and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to COLCHICINE; VINCRISTINE; and VINBLASTINE. alpha-Tubulin,beta-Tubulin,delta-Tubulin,epsilon-Tubulin,gamma-Tubulin,alpha Tubulin,beta Tubulin,delta Tubulin,epsilon Tubulin,gamma Tubulin
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis

Related Publications

Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
October 2021, Bioorganic chemistry,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
December 2022, European journal of medicinal chemistry,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
December 2005, Bioorganic & medicinal chemistry letters,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
September 2017, Scientific reports,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
March 2019, European journal of medicinal chemistry,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
April 2022, Bioorganic chemistry,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
January 2017, European journal of medicinal chemistry,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
May 2007, Molecules (Basel, Switzerland),
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
November 2015, Molecular diversity,
Xian-Sen Huo, and Xie-Er Jian, and Jie Ou-Yang, and Lin Chen, and Fang Yang, and Dong-Xin Lv, and Wen-Wei You, and Jin-Jun Rao, and Pei-Liang Zhao
March 2006, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!