Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies
The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoi...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/8/1808 |
| _version_ | 1797538206558715904 |
|---|---|
| author | Vladimir A. D’yakonov Alexey A. Makarov Lilya U. Dzhemileva Ilfir R. Ramazanov Elina Kh. Makarova Usein M. Dzhemilev |
| author_facet | Vladimir A. D’yakonov Alexey A. Makarov Lilya U. Dzhemileva Ilfir R. Ramazanov Elina Kh. Makarova Usein M. Dzhemilev |
| author_sort | Vladimir A. D’yakonov |
| collection | DOAJ |
| description | The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP). |
| first_indexed | 2024-03-10T12:27:14Z |
| format | Article |
| id | doaj.art-a56145cdacc84fa6a630469dbf84bfed |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T12:27:14Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a56145cdacc84fa6a630469dbf84bfed2023-11-21T14:56:51ZengMDPI AGCancers2072-66942021-04-01138180810.3390/cancers13081808Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting StudiesVladimir A. D’yakonov0Alexey A. Makarov1Lilya U. Dzhemileva2Ilfir R. Ramazanov3Elina Kh. Makarova4Usein M. Dzhemilev5Institute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences pr. Oktyabrya 141, 450075 Ufa, RussiaThe first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP).https://www.mdpi.com/2072-6694/13/8/1808Z,Z,Z-trienoic acidscross-cyclomagnesiationtopoisomerase inhibitorsanticancer activityapoptosiscell signaling |
| spellingShingle | Vladimir A. D’yakonov Alexey A. Makarov Lilya U. Dzhemileva Ilfir R. Ramazanov Elina Kh. Makarova Usein M. Dzhemilev Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies Cancers Z,Z,Z-trienoic acids cross-cyclomagnesiation topoisomerase inhibitors anticancer activity apoptosis cell signaling |
| title | Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies |
| title_full | Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies |
| title_fullStr | Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies |
| title_full_unstemmed | Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies |
| title_short | Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies |
| title_sort | natural trienoic acids as anticancer agents first stereoselective synthesis cell cycle analysis induction of apoptosis cell signaling and mitochondrial targeting studies |
| topic | Z,Z,Z-trienoic acids cross-cyclomagnesiation topoisomerase inhibitors anticancer activity apoptosis cell signaling |
| url | https://www.mdpi.com/2072-6694/13/8/1808 |
| work_keys_str_mv | AT vladimiradyakonov naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies AT alexeyamakarov naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies AT lilyaudzhemileva naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies AT ilfirrramazanov naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies AT elinakhmakarova naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies AT useinmdzhemilev naturaltrienoicacidsasanticanceragentsfirststereoselectivesynthesiscellcycleanalysisinductionofapoptosiscellsignalingandmitochondrialtargetingstudies |