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.
Yan A Ivanenkov  1 ,  Sergei V Vasilevski  2 ,  Elena K Beloglazkina  3 ,  Maksim E Kukushkin  2 ,  Alexey E Machulkin  3 ,  Mark S Veselov  4 ,  Nina V Chufarova  5 ,  Elizaveta S Chernyaginab  6 ,  Anton S Vanzcool  7 ,  Nikolay V Zyk  2 ,  Dmitry A Skvortsov  2 ,  Anastasia A Khutornenko  8 ,  Alexander L Rusanov  9 ,  Alexander G Tonevitsky  10 ,  Olga A Dontsova  11 ,  Alexander G Majouga  12
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.