Proapoptotic modification of substituted isoindolinones as MDM2-p53 inhibitors

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5197-5202. doi: 10.1016/j.bmcl.2017.10.049.

Tatyana A Grigoreva ¹, Daria S Novikova ², Alexey V Petukhov ², Maxim A Gureev ³, Alexander V Garabadzhiu ², Gerry Melino ⁴, Nickolai A Barlev ⁵, Vyacheslav G Tribulovich ²

Affiliations

1 St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia. Electronic address: rozentatiana@gmail.com.
2 St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia.
3 St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia; I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia.
4 University of Rome Tor Vergata, Rome 00173, Italy.
5 Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia.

PMID: 29089230 DOI: 10.1016/j.bmcl.2017.10.049

Abstract

A series of novel amino acid ester derivatives of 2,3-substituted isoindolinones was synthesized and evaluated for p53-mediated apoptotic activity. The rationale for augmentation of the target activity of 2,3-substituted isoindolinones was based on the introduction of new fragments in the structure of the inhibitor that would provide additional binding sites in the hydrophobic cavity of MDM2. To select for the anticipated modifications we employed molecular docking. Synthesized molecules were evaluated for their ability to induce Apoptosis in two Cancer cell lines and their derivatives with different status of p53 (colorectal HCT116 and osteosarcoma U2OS cells) by Annexin V staining. The target activity was estimated using high-content imaging system Operetta. Valine and phenylglycine ester derivatives were identified as potentially active MDM2-p53 inhibitors.

Keywords

Apoptosis; Computer modelling; MDM2; P53; Protein-protein interaction.

Name
Email *

	Sorry, but the email address you supplied was invalid.