title: Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype.
abstract: We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) demonstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this conclusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers of mitotic cells following treatment of a leukemia cell line.
authors.affiliation: Department of Chemistry, St. Petersburg State University, Peterhof 198504, Russia. Electronic address: m.krasavin@hotmail.com.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
authors.affiliation: ORCHIMED, Institute of Physiologically Active Compounds, Chernogolovka, Moscow Region 142432, Russia.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Sosnov
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia.
authors.forename: Ruben
authors.initials: R
authors.lastname: Karapetian
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia.
authors.forename: Igor
authors.initials: I
authors.lastname: Konstantinov
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Soldatkina
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Godovykh
authors.affiliation: Peoples' Friendship University of Russia, Moscow 117198, Russia.
authors.forename: Fedor
authors.initials: F
authors.lastname: Zubkov
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; The University of Virginia, Charlottesville, VA 22908, USA; The Discovery Chemistry Project, Bethesda, MD 20824, USA. Electronic address: akhaa@yahoo.com.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Gakh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000596934:4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D010880:Piperidines; D014404:Tubulin; D050257:Tubulin Modulators
keywords: Chemotherapeutic agents; DU-145; Prostate cancer; Rational single-molecule polypharmacy; Screening; Tubulin inhibitor