Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity

Gaur, Rashmi; Pathania, Anup Singh; Malik, Fayaz; Bhakuni, R. S.; Verma, Rajesh

doi:10.1016/j.ejmech.2016.06.035

Cited by 51 publications

(25 citation statements)

References 70 publications

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“…150 In the same vein, novel formulations such as synthetic dimers, trimers, and drug hybrids with quinolines as well as other compounds have also emerged as viable methods of drastically enhancing drug effectiveness as well as overcoming drug resistance and improving pharmacokinetic properties. [152][153][154][155][156][157][158][159][160][161] Many of these synthetic derivatives have been extensively reviewed by the Tsogoeva group. 162 Another emerging approach focuses on targeted drug delivery to specific cellular compartments and organelles.…”

Section: Enhancement Of Anticancer Activitymentioning

confidence: 99%

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Wong

Kalesh

et al. 2017

Medicinal Research Reviews

198

139

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Section: Enhancement Of Anticancer Activitymentioning

confidence: 99%

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Wong

Kalesh

et al. 2017

Medicinal Research Reviews

198

139

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“…The Figure 6 shows the results from the IC 50 ] to determine the stage specificities of the compounds by measuring the concentrationdependent growth of schizonts and rings following incubation with the two compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Changes in mitochondrial membrane potential were measured using rhodamine 123 (excitation wavelength, 511 nm; emission wavelength, 534 nm), a membranepermeating cationic fluorescent dye (49), which accumulates by electrostatic attraction in the mitochondria because of its negative transmembrane potential. A change in the dye's concentration in the mitochondria is caused by a depolarization event and can be visualized as a shift in the fluorescence intensity of rhodamine 123 (50). Draq5 (excitation wavelength, 647 nm; emission wavelength, Ͼ665 nm) is a far-red fluorescent DNA dye which is cell permeating and was used to distinguish the parasites in flow cytometry in the allophycocyanin (APC)-Cy7-A channel.…”

Section: Lead Optimization Of Dehydroemetine For Malariamentioning

confidence: 99%

Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

Panwar

Burusco

Abubaker

et al. 2020

Antimicrob Agents Chemother

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Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC 50 ], 47 nM Ϯ 2.1 nM [mean Ϯ standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have lesscardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (Ϫ)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (Ϫ)-S,S-dehydroisoemetine. (Ϫ)-R,Sdehydroemetine (IC 50 71.03 Ϯ 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (Ϫ)-S,S-dehydroisoemetine (IC 50 , 2.07 Ϯ 0.26 M), which loses its potency due to the change of configuration at C-1=. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (Ϫ)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (Ϫ)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

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“…The guanidine‐containing dimers 23 (IC 50 : 0.02–2.08 μM, MTT assay) demonstrated considerable activity against A549, HT‐29, and MDA‐MB‐231 cancer cell lines, and all of them were more potent than dihydroartemisinin (IC 50 : 7.8–12.0 μM) . The SAR revealed that all guanidine‐containing dimers were more active than the corresponding monomers, whereas the chalcone‐containing dimers were less potent than the corresponding monomers . Moreover, the bis‐substituted dimer 23a (IC 50 : 0.02–1.42 μM) was generally more potent than the monosubstituted analogs against A549, HT‐29, and MDA‐MB‐231 cancer cell lines.…”

Section: Ether‐tethered Artemisinin‐derived Dimersmentioning

confidence: 99%

Artemisinin‐derived dimers as potential anticancer agents: Current developments, action mechanisms, and structure–activity relationships

Zhang

2019

Archiv der Pharmazie

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Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects.Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure-activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer.This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers.

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Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity

Cited by 51 publications

References 70 publications

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

Artemisinin‐derived dimers as potential anticancer agents: Current developments, action mechanisms, and structure–activity relationships

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