Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Krasavin, Mikhail¹  Sosnov, Andrey V.²  Karapetian, Ruben³  Konstantinov, Igor³  Soldatkina, Olga³  Godovykh, Elena³  Zubkov, Fedor⁴  Bai, Ruoli⁵  Hamel, Ernest⁵  Gakh, Andrei A.^6,7,8 

[1] St Petersburg State Univ, Dept Chem, Peterhof 198504, Russia

[2] Russian Acad Sci, Inst Physiol Act Cpds, ORCHIMED, Chernogolovka 142432, Moscow Region, Russia

[3] Chem Div Res Inst, Chimki 114401, Moscow Region, Russia

[4] Peoples Friendship Univ Russia, Moscow 117198, Russia

[5] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[6] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA

[7] Univ Virginia, Charlottesville, VA 22908 USA

[8] Discovery Chem Project, Bethesda, MD 20824 USA

关键词: Prostate cancer;    DU-145;    Screening;    Chemotherapeutic agents;    Rational single-molecule polypharmacy;    Tubulin inhibitor;   

DOI  :  10.1016/j.bmcl.2014.07.089

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free