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Novel nannocystin A analogues as anticancer therapeutics: Synthesis, biological evaluations and structure-activity relationship studies.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 May 15; Vol. 170, pp. 99-111. Date of Electronic Publication: 2019 Mar 10. - Publication Year :
- 2019
-
Abstract
- Nannocystin A is a novel 21-membered macrocyclic lactam that targets eukaryotic translation elongation factor 1α (eEF1A) and displays potent antiproliferative activities. Herein, a series of nannocystin A analogues were synthesized and their structure-activity relationship (SAR) were established based on the MTT assay and western blotting analysis. The SAR enabled us to identify a structurally simplified nannocystin A analogue LQ18, which exhibited potent antiproliferative activities with IC <subscript>50</subscript> values ranging from 4.3 to 48 nM against the tested cell lines, and inhibited eEF1A1 expression in A549 cell line. LQ18 arrested cell cycle at G2 phase and induced A549 cell apoptosis via up-regulation of caspase-3, caspase-9 and bax protein expressions in a dose-dependent manner, while it significantly decreased the bcl-2 expression. Collectively, these data demonstrated that LQ18 could be a promising lead for the development of structurally novel eEF1A1 inhibitor for cancer treatment.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- A549 Cells
Antineoplastic Agents chemical synthesis
Apoptosis drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
Humans
Macrocyclic Compounds chemical synthesis
Neoplasms drug therapy
Neoplasms pathology
Peptide Elongation Factor 1 analysis
Structure-Activity Relationship
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Macrocyclic Compounds chemistry
Macrocyclic Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 170
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30878835
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.03.011