Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity

D’yakonov, Vladimir A.; Dzhemileva, Lilya U.; Макаров, А. А.; Mulukova, Alfiya R.; Baev, Dmitry S.; Хуснутдинова, Э. К.; Толстикова, Т. Г.; Джемилев, У. М.

doi:10.1016/j.bmcl.2015.04.011

Cited by 39 publications

(12 citation statements)

References 23 publications

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“…As expected from the previous literature, where very long-chain Δ5,9 FA were reported to be good inhibitors of h TopI [10–12], acids 1a – 1b also proved to be very good inhibitors of h TopIB (EC 50 ~ 4.6 μM). Since we did not have the corresponding C 27 non-methoxylated Δ5,9 FA at hand, it was not possible to test how the C-2 methoxy group affected the binding to h TopIB.…”

Section: Discussionsupporting

confidence: 85%

“…For example, it was reported that 5,9–27:2 effectively inhibits h TopI with an IC 50 of 0.86 μM [10]. Other equally cytotoxic compounds include the 5,9–20:2 (IC 50 > 0.1 μM), 5,9–28:2 (IC 50 = 1.3 μM), the methyl branched 23-Me-5,9–26:2 (IC 50 = 1.1 μM) and the fully synthetic (5 Z ,9 Z )-11-phenyl-5,9-undecadienoic acid (IC 50 = 0.7 μM) [10–12]. All of these FA, which have shown inhibitory activity against h TopI, do not have any structural characteristics similar to the well-known DNA h TopI inhibitors, such as camptothecin (CPT).…”

Section: Introductionmentioning

confidence: 99%

“…All of these FA, which have shown inhibitory activity against h TopI, do not have any structural characteristics similar to the well-known DNA h TopI inhibitors, such as camptothecin (CPT). The mechanism of h TopI inhibition can be associated with the direct interaction of these FA with the h TopI enzyme by binding in close proximity of the active site, thus inhibiting the DNA cleavage by a tyrosine, while still allowing the enzyme-DNA interaction [12]. It is of interest to mention that the combination of both 22-Me-5,9–24:2 and 23-Me-5,9–24:2 displays cytotoxicity against mouse Ehrlich carcinoma cells (ED 50 = 1.9 μg/mL) and shows hemolytic effect on mouse erythrocytes [4].…”

Section: Introductionmentioning

confidence: 99%

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Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Carballeira

Montano

Amador

et al. 2015

Lipids

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The novel fatty acids (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic acid (1a) and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid (1b) were isolated in 80% purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography-mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP-1 and HepG2 cells with EC50’s between 41 and 35 μg/mL. Apoptosis was not the preferred mode of cell death induced by 1a–1b in the THP-1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC50 = 1.8 μg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC50 = 0.17 mg/mL) and free living promastigotes (IC50 = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC50 = 5.1 μg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Carballeira

Montano

Amador

et al. 2015

Lipids

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“…A Topo I inhibitory assay 13 was employed as an initial screen to establish the efficacy (or otherwise) of the abovementioned bivalent securinine mimetics. In this assay, CPT, an established Topo I inhibitor, 3 was used as the positive control.…”

Section: Resultsmentioning

confidence: 99%

Novel bivalent securinine mimetics as topoisomerase I inhibitors

et al. 2017

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“…Interest in such 5Z,9Z‐diene fatty acids arises from their antimalarial, antimicrobial, antiviral and antitumor activity . It was subsequently illustrated, that introduction of a lipophilic fragment in the form of steroid framework into the molecule of dienoic acid results in an increase of antitumor activity against HeLa, Hek293, U937, Jurkat, K562 cells, by impacting effectively, among others, the cell cycle via inhibition of topoisomerases I and II.…”

Section: Methodsmentioning

confidence: 99%

Hybrid Molecules Based on C₆₀ Fullerene and 5Z,9Z‐Dienoic Acids: Synthesis and Cytotoxic Activity

et al. 2019

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The present research addresses synthesis of methanofullerenes containing 5Z,9Z-dienoic acid molecules applying the Bingel and Bingel-Hirsch reactions. The cytotoxic activity of the synthesized methanofullerenes against Jurkat, K562, U937, HL60 tumour cells was under study. Hybrid methanofullerenes containing dienoic acids were found to exhibit high in vitro cytotoxicity against these tumour cell lines, produce phasespecific cytotoxic effect during the S and G2 phases of the cell cycle, and are also effective inducers of apoptosis.Building effective systems for targeted drug delivery in the development of anticancer drugs is one of the major challenges of modern pharmacology. This is due to the fact that most antitumor drugs are highly toxic and lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts.No coincidence is the fact that the range of nanoscale delivery vectors of anticancer drugs has expanded significantly since the discovery of fullerenes in 1985. The size, shape and high lipophilicity of C 60 fullerene enable it to penetrate rather easily through cell membranes and are an ideal combination of properties for use as a vector for targeted drug delivery.To date, the transport properties of C 60 fullerene have been successfully demonstrated on a wide range of different pharmaceutical products and anticancer drugs. A perfect example of the use of C 60 fullerene as a means of anticancer drug delivery with the aim of increasing their selectivity is the production of complexes and hybrids with doxorubicin. [1][2][3][4][5][6][7][8] Individual doxorubicin is characterized by low selectivity and cardiotoxicity, its fullerene complex increases both the rate of penetration into cancer cells by 20-30% and the effectiveness increases by 1.5-2 times. [1] The conjugate of doxorubicin with C 60 reduces the tumor volume by 40-60% in vivo compared to an individual doxorubicin, thus increasing life expectancy of mice by 2.5 times. [1,2] Furthermore, enhanced efficiency of the conjugate does not increase the side effects of the initial preparation. [4,5] Chemical binding of C 60 fullerene and its derivatives with doxorubicin does not produce obvious therapeutic effect of this kind, [6,7] but there is still a significant decline in the toxicity of the initial anticancer drug. [7] The main difference between the hybrid and the original doxorubicin molecules is that the hybrid, after penetrating the cell, primarily accumulates in the cytoplasm, and not in the nucleus. [8] Along with doxorubicin, C 60 fullerene complexes and hybrids were also prepared with paclitaxel, [9,10] docetaxel, [11 ] and cisplatin. [12,13] Increased effectiveness of the corresponding drugs was reached with achieved both in vivo and in vitro experiments. Meanwhile, when comparing the therapeutic effect, a considerable decline in the toxicity of these drugs was registered as well.Recently, our research group developed an efficient onepot method for the synthesis of 5Z,9Z-dienoic acids with a yield of ∼ 70% an...

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Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity

Cited by 39 publications

References 23 publications

Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Novel bivalent securinine mimetics as topoisomerase I inhibitors

Hybrid Molecules Based on C₆₀ Fullerene and 5Z,9Z‐Dienoic Acids: Synthesis and Cytotoxic Activity

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Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity

Cited by 39 publications

References 23 publications

Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Novel bivalent securinine mimetics as topoisomerase I inhibitors

Hybrid Molecules Based on C60 Fullerene and 5Z,9Z‐Dienoic Acids: Synthesis and Cytotoxic Activity

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Hybrid Molecules Based on C₆₀ Fullerene and 5Z,9Z‐Dienoic Acids: Synthesis and Cytotoxic Activity