Journal
BIOORGANIC CHEMISTRY
Volume 99, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.103832
Keywords
Macrodiolides; Anticancer activity; Mitochondrial apoptosis; Cell cycle; Cytotoxicity
Funding
- Russian Science Foundation [17-73-10136]
- Russian Science Foundation [17-73-10136] Funding Source: Russian Science Foundation
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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 alpha,omega-diols with alpha,omega-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 homocyclomagnesiation 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.
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