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

Mikhail Krasavin; Andrey V Sosnov; Ruben Karapetian; Igor Konstantinov; Olga Soldatkina; Elena Godovykh; Fedor Zubkov; Ruoli Bai; Ernest Hamel; Andrei A Gakh

doi:10.1016/j.bmcl.2014.07.089

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

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4477-4481. doi: 10.1016/j.bmcl.2014.07.089. Epub 2014 Aug 8.

Authors

Affiliations

¹ Department of Chemistry, St. Petersburg State University, Peterhof 198504, Russia. Electronic address: m.krasavin@hotmail.com.
² ORCHIMED, Institute of Physiologically Active Compounds, Chernogolovka, Moscow Region 142432, Russia.
³ Chemical Diversity Research Institute, Khimki, Moscow Region 114401, Russia.
⁴ Peoples' Friendship University of Russia, Moscow 117198, Russia.
⁵ 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.
⁶ 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.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship
Tubulin / metabolism*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide
Antineoplastic Agents
Oxadiazoles
Piperidines
Tubulin
Tubulin Modulators

Grants and funding

Z99 CA999999/Intramural NIH HHS/United States