Natural compounds with bis-methylene-interrupted Z-double bonds: plant sources, strategies of total synthesis, biological activity, and perspectives

D’yakonov, Vladimir A.; Dzhemileva, Lilya U.; Джемилев, У. М.

doi:10.1007/s11101-020-09685-6

Cited by 18 publications

(11 citation statements)

References 161 publications

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“…For assessing the influence on topoisomerase II of the studied derivatives of hybrid molecules based on 5 Z ,9 Z -diene acids, the investigation into possible DNA damage in Jurkat tumor cells was carried out. We had previously shown that various compounds containing a diene moiety can affect their ability to inhibit topoisomerase II [ 7 , 23 , 24 , 25 , 26 , 27 , 33 , 34 , 35 , 36 , 37 , 38 ]. Changes in the concentration of total and phosphorylated proteins H2A.X allow at the same time confirming the target specificity of the phosphorylation event of this histone class.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

et al. 2021

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For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5Z,9Z)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5Z,9Z-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2–4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented.

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Section: Resultsmentioning

confidence: 99%

“…Flora and fauna are readily available sources of structurally diverse bioactive compounds [ 4 , 5 , 6 , 7 ]. It is not surprising that chemical modifications have become one of the most promising trends in the search for physiologically active compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

et al. 2021

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“…It is known that the 1 Z ,5 Z- diene moiety is encountered in numerous biologically active compounds, for example, fatty 5 Z ,9 Z- dienoic acids, lembehynes, acetogenins, and insect pheromones . Our previous studies were related to the development of efficient stereoselective syntheses of cis,cis -unsaturated natural and synthetic compounds, which exhibit antitumor, antibacterial, and neuritogenic properties. − …”

Section: Introductionmentioning

confidence: 99%

New Polyether Macrocycles as Promising Antitumor Agents─Targeted Synthesis and Induction of Mitochondrial Apoptosis

Islamov,

Dzhemileva,

Gaisin

et al. 2024

ACS Omega

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A series of previously unknown aromatic polyether macrodiolides containing a cis,cis-1,5-diene moiety in the molecule were synthesized in 47−74% yields. Macrocycle compounds were first obtained by intermolecular esterification of aromatic polyether diols with α,ω-alka-nZ,(n+4)Z-dienedioic acids mediated by N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl) and 4-(dimethylamino)pyridine (DMAP). For the synthesized compounds, studies of cytotoxicity on tumor (Jurkat, K562, U937), conditionally normal (HEK293) cell lines, and normal fibroblasts were carried out. CC50 was determined, and the therapeutic selectivity index of cytotoxic action (SI) in comparison with normal fibroblasts was evaluated. With the involvement of modern methods of flow cytometry for the most promising macrocycles, their effect on mitochondria and the cell cycle was investigated. It was found that a new macrocycle exhibits pronounced apoptosis-inducing activity toward Jurkat cells and can retard cell division by blocking at the G1/S checkpoint. Also, it was shown that the synthesized macrodiolides influence mitochondria due to their high ability to penetrate the mitochondrial membrane.

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“…Among numerous classes of compounds, polyunsaturated fatty acids attract special attention of researchers, as they are significant for the vital activity of all living organisms, as they are precursors of potent eicosanoid bioregulators such as prostaglandins and leukotrienes [ 1 , 2 , 3 , 4 ], are involved in lipid metabolism [ 5 ], exhibit antihistaminic [ 6 ] and anti-inflammatory effects [ 7 ], possess antitumor properties [ 8 , 9 , 10 ] and stimulate immune response [ 11 ]. They are widely used for prevention and treatment of cardiovascular diseases [ 11 , 12 , 13 ] and are promising for the treatment of brain diseases [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies

D’yakonov

Макаров

Dzhemileva

et al. 2021

Cancers

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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).

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Natural compounds with bis-methylene-interrupted Z-double bonds: plant sources, strategies of total synthesis, biological activity, and perspectives

Cited by 18 publications

References 161 publications

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

New Polyether Macrocycles as Promising Antitumor Agents─Targeted Synthesis and Induction of Mitochondrial Apoptosis

Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies

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