New 1Z,5Z-diene macrodiolides: Catalytic synthesis, anticancer activity, induction of mitochondrial apoptosis, and effect on the cell cycle
| Autor: | Vladimir A. D’yakonov, Ilgiz I. Islamov, Milyausha M. Yunusbaeva, Lilya U. Dzhemileva, Usein M. Dzhemilev |
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| Rok vydání: | 2020 |
| Předmět: |
Cell Survival
Stereochemistry Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Jurkat cells HeLa Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Moiety Molecular Biology Cells Cultured Cell Proliferation Jones oxidation Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Cell Cycle Organic Chemistry Tetrahydropyran biology.organism_classification Mitochondria 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Pyran Stereoselectivity Macrolides Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic Chemistry. 99:103832 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.103832 |
| Popis: | An original scheme was developed for the synthesis of previously undescribed unsaturated macrodiolides containing a 1Z,5Z-diene moiety in 44–80% yields and with high stereoselectivity (>95%) based on the intermolecular esterification of α,ω-diols with α,ω-alka-nZ,(n + 4)Z-dienedicarboxylic acids (1,12-dodeca-4Z,8Z-dienedicarboxylic acid, 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid, 1,18-octadeca-7Z,11Z-dienedicarboxylic acid) catalyzed by hafnium triflate [Hf(OTf)4]. The unsaturated dicarboxylic acids were prepared via homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol.%) and the subsequent Jones oxidation of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The thus prepared macrodiolides exhibit high cytotoxic activity in vitro against Jurkat, K562, U937, Hek293 and HeLa cancer cell lines. It was found that induction of the programmed cell death in Jurkat cells by macrodiolides corresponds to the mitochondrial apoptosis pathway. Also, it was shown that the prepared macrodiolides efficiently suppress phosphorylation of Akt and p38 kinases and CREB transcription factor in cancer cells. |
| Databáze: | OpenAIRE |
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