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Proapoptotic modification of substituted isoindolinones as MDM2-p53 inhibitors.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Grigoreva TA,Novikova DS,Petukhov AV,Gureev MA,Garabadzhiu AV,Melino G,Barlev NA,Tribulovich VG

doi

10.1016/j.bmcl.2017.10.049

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

5197-5202

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)31043-0

journal_volume

27

pub_type

杂志文章

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