Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents
| Autor: | Janki Shah-Mittal, Daniel Romo, Ken Hull, Jing Li, Sai Shilpa Kommaraju, Mingzhao Zhu, Jun O. Liu, Woon-Kai Low |
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| Rok vydání: | 2014 |
| Předmět: |
Tertiary amine
Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Article Eukaryotic translation Eukaryotic initiation factor Drug Discovery medicine Side chain Humans Eukaryotic Initiation Factors Peptide Chain Initiation Translational Molecular Biology Cell Proliferation Biological Products Chemistry Organic Chemistry Translation (biology) In vitro Thiazoles Mechanism of action eIF4A Epoxy Compounds Molecular Medicine Macrolides medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:116-125 |
| ISSN: | 0968-0896 |
| Popis: | A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19–C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells. |
| Databáze: | OpenAIRE |
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