Synthesis and Antiproliferative Activity of Conjugates of Anthracycline Antibiotics with Sesquiterpene Lactones of the Elecampane

Semakov, A. V.; Аникина, Л. В.; Afanasyeva, S. V.; Pukhov, S. A.; Клочков, С. Г.

doi:10.1134/s1068162018040167

Cited by 7 publications

(5 citation statements)

References 10 publications

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“…Currently, lots of analogs have been synthesized chemically or transformed microbiologically, among which many retain the bioactivity of Ala while some even attain new bioactivities absent from Ala, such as the inhibition of pulmonary fibrosis through TGF-β1 pathway (Cantrell et al, 2010;Kumar et al, 2019;Li et al, 2018;Xin et al, 2008). Through Michael reaction, Ala can also be conjugated to substituted piperazines or antibiotics to enhance the efficacy and reduce the cytotoxicity of drugs, such as daunorubicin and doxorubicin (Pukhov et al, 2019;Semakov et al, 2018). All these suggest that Ala is a promising molecule with diverse therapeutic potentials.…”

Section: Discussionmentioning

confidence: 99%

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

et al. 2021

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Alantolactone (Ala) is a sesquiterpene lactone that can be isolated from many herbal plants belonging to Asteraceae. Besides the antimicrobial activities against bacteria, fungi and viruses, Ala has also demonstrated significant antiinflammatory effects in various models by inhibiting NF-κB and MAPKs to decrease the pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The antitumor effects of Ala have been demonstrated in vitro and in vivo via inducing intrinsic apoptosis, oxidative stress, ER stress, cell cycle arrest and inhibiting autophagy and STAT3 phosphorylation, which are also involved in its combination or synergy with other antitumor drugs. Ala also has neuroprotective activity through attenuating oxidative stress and inflammation, besides its modulation of glucose and lipid metabolism. This review summarizes the recent advances of the pharmacological effects of Ala, including anti-inflammatory, antitumor, antimicrobial, neuroprotective activities, as well as the underlying mechanisms.Ala might be employed as a potential lead to develop drugs for multiple diseases.

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Section: Discussionmentioning

confidence: 99%

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

et al. 2021

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“…The natural sesquiterpene lactones ( 1 ) and ( 2 ) were isolated from the roots of elecampane Inula helenium L. according to the method we developed earlier [ 23 ]. Alloalantholactone ( 3 ) was obtained by isomerization of isoalantholactone ( 1 ) under the action of a 5-fold excess of trifluoroacetic acid (in chloroform) [ 22 ]. Epoxylactones ( 4 ), ( 5 ), ( 6 ) were obtained from them by the action of peracetic acid according to the procedures from [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…Anthracycline antibiotics conjugates ( 1a ), ( 2a ), ( 4a) , ( 5a ), ( 6a ), ( 1b ), ( 3b ), ( 4b ), ( 5b ), ( 6b ) were obtained as described earlier; the spectral characteristics corresponded to the literature data [ 20 , 21 , 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The anthracycline antibiotics doxorubicin ( a ) and daunorubicin ( b ) were modified with sesquiterpene lactones—isoalantholactone ( 1 ), alantolactone ( 2 ), alloalantholactone ( 3 ), epoxy-isoalantholactone ( 4 ), epoxyalantholactolactone ( 5 ), epoxyalloalantholactone ( 6 ), 6-hydroxyxanthanodiene ( 7 ), alanthodiene ( 8 ). Conjugates 1-6a-b were obtained in our previous works [ 20 , 21 , 22 ]; compounds 7a , b and 8a , b were first obtained and studied. Their cytotoxic and antiproliferative properties in relation to tumor cell lines were evaluated and their influence on key aspects of formation of cytotoxicity—mitochondrial functional characteristics (mitochondrial swelling, membrane potential, and mitochondrial respiratory chain complexes) as well as the glycolytic function parameters of HeLa tumor cells— was studied.…”

Section: Introductionmentioning

confidence: 99%

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N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects

et al. 2021

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Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.

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“…Since most sesquiterpene lactones contain an activated exo -methylene moiety, which readily reacts with nucleophiles by the Michael reaction, this makes it quite easy to obtain bipharmacophoric compounds on their basis [ 14 ]. For this purpose, various amines [ 15 , 16 ] such as fragments of drugs can be used, for example, the conjugates of lactones with anthracycline antibiotics which show both increased efficiency and reduced cardiotoxicity [ 17 ]. Interesting derivatives are described in [ 18 ], where the sesquiterpene lactone parthenolide was combined in one molecule with the drugs cytarabine and melphalan.…”

Section: Introductionmentioning

confidence: 99%

Design of Conjugates Based on Sesquiterpene Lactones with Polyalkoxybenzenes by “Click” Chemistry to Create Potential Anticancer Agents

et al. 2022

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Using the methodology of “click” chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a–d with a long spacer and substances containing dehydrocostuslactone 10a–d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.

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Synthesis and Antiproliferative Activity of Conjugates of Anthracycline Antibiotics with Sesquiterpene Lactones of the Elecampane

Cited by 7 publications

References 10 publications

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects

Design of Conjugates Based on Sesquiterpene Lactones with Polyalkoxybenzenes by “Click” Chemistry to Create Potential Anticancer Agents

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