Functionalisation of Artemisinin and Its Ring-contracted Derivatives

Neck, Tine Van; Mierloo, Sarah Van; Dehaen, Wim

doi:10.3390/12030395

Cited by 9 publications

(5 citation statements)

References 9 publications

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“…The synthesis of artemalogues 6 and 7 was shown in Scheme . Starting from commercial substrate 3 , acid 8 and ring-contracted acid 10 were prepared via several steps according to literature procedures. Condensation of 8 with 4-chloro-3-(pyridin-2-yl)aniline in the presence of 1-[bis(dimethylamino) methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU) and 1-hydroxy-7-azabenzotriazole (HOAT) delivered the hybrid product 6 in 62% yield.…”

Section: Resultsmentioning

confidence: 99%

“…NOE were used in the structural assignment. Compounds 8 , 10 , 12 , 14 , 42 , 44 , 55 , 56 , 58a , and 59 were prepared according to corresponding literature procedures. HPLC analysis was conducted for all bioassayed compounds on an Agilent Technologies 1260 series LC system (Agilent ChemStation Rev.A.10.02; ZORBAX-C18, 4.6 mm × 150 mm, 5 μM, MeOH (0.1% DEA)/H 2 O, rt) with two ultraviolet wavelengths (UV 254 and 214 nm).…”

Section: Methodsmentioning

confidence: 99%

“…The residue was purified by silica column chromatography (CH 2 Cl 2 / EtOAc 2:1) to give 30 as white solid (31 mg, 30%). 1 Synthesis of (R)-N-(4-Chloro-3-(pyridin-2-yl)phenyl)-2-((4aS,5R,8-R,8aS)-5-methyl-1-phenyl-4,4a,5,6,7,8,8a,9-octahydro-1H-benzo[f ]indazol-8-yl)propanamide (33). A solution of 14 (238 mg, 1.0 mmol) in THF (10 mL) was cooled to 0 °C.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

et al. 2016

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A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent, with an IC value of 9.53 nM against the Hh signaling pathway. Complementary mechanism studies confirmed that 65 inhibits Hh signaling pathway by targeting Smo and shares the same binding site as that of the tool drug cyclopamine. Meanwhile, 65 has a good plasma exposure and an acceptable oral bioavailability. Dose-dependent antiproliferative effects were observed in ptch+/-;p53-/- medulloblastoma cells, and significant tumor growth inhibitions were achieved for 65 in the ptch+/-;p53-/- medulloblastoma allograft model.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

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Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

et al. 2016

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“…We next assessed the antiviral activity of novel ART derivatives (all were recently synthesized with the aim to improve the anti-malarial properties of this class of drugs [20] ) belonging to three different categories (AJ, TVN and DW). The chemical structures of ART and the compounds of category AJ are depicted in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Artemisinin analogues ( Fig. 1 and 2 ) were synthesized by methods that will be reported elsewhere [20] .…”

Section: Methodsmentioning

confidence: 99%

Artemisinin Analogues as Potent Inhibitors of In Vitro Hepatitis C Virus Replication

et al. 2013

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We reported previously that Artemisinin (ART), a widely used anti-malarial drug, is an inhibitor of in vitro HCV subgenomic replicon replication. We here demonstrate that ART exerts its antiviral activity also in hepatoma cells infected with full length infectious HCV JFH-1. We identified a number of ART analogues that are up to 10-fold more potent and selective as in vitro inhibitors of HCV replication than ART. The iron donor Hemin only marginally potentiates the anti-HCV activity of ART in HCV-infected cultures. Carbon-centered radicals have been shown to be critical for the anti-malarial activity of ART. We demonstrate that carbon-centered radicals-trapping (the so-called TEMPO) compounds only marginally affect the anti-HCV activity of ART. This provides evidence that carbon-centered radicals are not the main effectors of the anti-HCV activity of the Artemisinin. ART and analogues may possibly exert their anti-HCV activity by the induction of reactive oxygen species (ROS). The combined anti-HCV activity of ART or its analogues with L-N-Acetylcysteine (L-NAC) [a molecule that inhibits ROS generation] was studied. L-NAC significantly reduced the in vitro anti-HCV activity of ART and derivatives. Taken together, the in vitro anti-HCV activity of ART and analogues can, at least in part, be explained by the induction of ROS; carbon-centered radicals may not be important in the anti-HCV effect of these molecules.

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Heterocycles via Oxime Cycloadditions

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Topics in Heterocyclic Chemistry

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Functionalisation of Artemisinin and Its Ring-contracted Derivatives

Cited by 9 publications

References 9 publications

Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

Artemisinin Analogues as Potent Inhibitors of In Vitro Hepatitis C Virus Replication

Heterocycles via Oxime Cycloadditions

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