Design, synthesis and biological evaluation of novel potent MDM2/p53 small-molecule inhibitors

Yan A Ivanenkov; Sergei V Vasilevski; Elena K Beloglazkina; Maksim E Kukushkin; Alexey E Machulkin; Mark S Veselov; Nina V Chufarova; Elizaveta S Chernyaginab; Anton S Vanzcool; Nikolay V Zyk; Dmitry A Skvortsov; Anastasia A Khutornenko; Alexander L Rusanov; Alexander G Tonevitsky; Olga A Dontsova; Alexander G Majouga

doi:10.1016/j.bmcl.2014.09.070

Design, synthesis and biological evaluation of novel potent MDM2/p53 small-molecule inhibitors

Bioorg Med Chem Lett. 2015 Jan 15;25(2):404-9. doi: 10.1016/j.bmcl.2014.09.070. Epub 2014 Oct 2.

Authors

Yan A Ivanenkov¹, Sergei V Vasilevski², Elena K Beloglazkina³, Maksim E Kukushkin², Alexey E Machulkin³, Mark S Veselov⁴, Nina V Chufarova⁵, Elizaveta S Chernyaginab⁶, Anton S Vanzcool⁷, Nikolay V Zyk², Dmitry A Skvortsov², Anastasia A Khutornenko⁸, Alexander L Rusanov⁹, Alexander G Tonevitsky¹⁰, Olga A Dontsova¹¹, Alexander G Majouga¹²

Affiliations

¹ ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA; Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, InstitutskiPereulok 9, Moskovskaya Oblast, Russia; Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia. Electronic address: [email protected].
² Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
³ Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia; Moscow State University of Mechanical Engineering (MAMI), Moscow, Russia.
⁴ Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, InstitutskiPereulok 9, Moskovskaya Oblast, Russia. Electronic address: [email protected].
⁵ Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, InstitutskiPereulok 9, Moskovskaya Oblast, Russia; National University of Science and Technology MISiS, Moscow 119049, Russia.
⁶ Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, InstitutskiPereulok 9, Moskovskaya Oblast, Russia.
⁷ ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA.
⁸ Belozersky Institute, Lomonosov Moscow State University, Leninskie Gory, 1/40, 119992, Moscow, Russia.
⁹ Moscow State University of Mechanical Engineering (MAMI), Moscow, Russia.
¹⁰ SRC Bioclinicum, Ugreshskaya str 2/85, Moscow 115088, Russia; P.A. Hertsen Moscow Research Oncology Institute, 2nd Botkinsky st., 125284 Moscow, Russia.
¹¹ Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia; Belozersky Institute, Lomonosov Moscow State University, Leninskie Gory, 1/40, 119992, Moscow, Russia.
¹² Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia; National University of Science and Technology MISiS, Moscow 119049, Russia. Electronic address: [email protected].

PMID: 25479770
DOI: 10.1016/j.bmcl.2014.09.070

Abstract

Regioselective synthesis, biological evaluation and 3D-molecular modeling for a series of novel diastereomeric 2-thioxo-5H-dispiro[imidazolidine-4,3-pyrrolidine-2,3-indole]-2,5(1H)-diones are described. The studied compounds have been tentatively identified as potent small molecule MDM2/p53 PPI inhibitors and can therefore be reasonably regarded as promising anticancer therapeutics.

Keywords: 3D molecular docking; Cell-based assay; Dispiro-indolinones; MDM2/p53; PPI inhibitors.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects*
Drug Design*
Humans
Models, Molecular
Molecular Dynamics Simulation
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / pathology
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / antagonists & inhibitors*

Substances

Antineoplastic Agents
Small Molecule Libraries
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2