Electrophilic C12 Building Blocks for Alkaloids: 1,1 Iterative Organoiron‐Mediated Routes to (±)‐Lycoramine and (±)‐Maritidine

Stephenson, G. R.; Roe, Caroline; Sandoe, Elizabeth J.

doi:10.1002/ejoc.201001394

Cited by 12 publications

(5 citation statements)

References 116 publications

(63 reference statements)

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“…Incartine [ 82 – 84 ] has shown significant neuroprotective effects against cell injury models in dopaminergic neuroblastoma SHSY5Y cells [ 85 ]. Lycoramine is a reversible cholinesterase inhibitor [ 86 ] and a modulator of nicotinic receptors, an important property in treating Alzheimer's and Parkinson's disease or neuroprotection against neurodegenerative disorders [ 87 ]. Nonetheless, these metabolites are isolated only in low amounts and therefore are not commercially available, representing an issue for thorough biological investigation.…”

Section: Discussionmentioning

confidence: 99%

Searching for plant-derived antivirals against dengue virus and Zika virus

Barbosa

Alves

Kohlhoff

et al. 2022

Virol J

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Background The worldwide epidemics of diseases as dengue and Zika have triggered an intense effort to repurpose drugs and search for novel antivirals to treat patients as no approved drugs for these diseases are currently available. Our aim was to screen plant-derived extracts to identify and isolate compounds with antiviral properties against dengue virus (DENV) and Zika virus (ZIKV). Methods Seven thousand plant extracts were screened in vitro for their antiviral properties against DENV-2 and ZIKV by their viral cytopathic effect reduction followed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, previously validated for this purpose. Selected extracts were submitted to bioactivity-guided fractionation using high- and ultrahigh-pressure liquid chromatography. In parallel, high-resolution mass spectrometric data (MSn) were collected from each fraction, allowing compounds into the active fractions to be tracked in subsequent fractionation procedures. The virucidal activity of extracts and compounds was assessed by using the plaque reduction assay. EC50 and CC50 were determined by dose response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral vs. cytotoxic activity. Purified compounds were used in nuclear magnetic resonance spectroscopy to identify their chemical structures. Two compounds were associated in different proportions and submitted to bioassays against both viruses to investigate possible synergy. In silico prediction of the pharmacokinetic and toxicity (ADMET) properties of the antiviral compounds were calculated using the pkCSM platform. Results We detected antiviral activity against DENV-2 and ZIKV in 21 extracts obtained from 15 plant species. Hippeastrum (Amaryllidaceae) was the most represented genus, affording seven active extracts. Bioactivity-guided fractionation of several extracts led to the purification of lycorine, pretazettine, narciclasine, and narciclasine-4-O-β-D-xylopyranoside (NXP). Another 16 compounds were identified in active fractions. Association of lycorine and pretazettine did not improve their antiviral activity against DENV-2 and neither to ZIKV. ADMET prediction suggested that these four compounds may have a good metabolism and no mutagenic toxicity. Predicted oral absorption, distribution, and excretion parameters of lycorine and pretazettine indicate them as candidates to be tested in animal models. Conclusions Our results showed that plant extracts, especially those from the Hippeastrum genus, can be a valuable source of antiviral compounds against ZIKV and DENV-2. The majority of compounds identified have never been previously described for their activity against ZIKV and other viruses.

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Section: Discussionmentioning

confidence: 99%

Searching for plant-derived antivirals against dengue virus and Zika virus

Barbosa

Alves

Kohlhoff

et al. 2022

Virol J

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“…Elemental analyses were performed with a Perkin–Elmer 2400 series II CHN analyzer. (2‐Dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)[2‐(2′‐amino‐1,1′‐biphenyl)]palladium(II) methanesulfonate (XPhos Pd G4), 2,2′‐bis(3‐chloropyridin‐2‐yl)biphenyl, 1‐bromo‐2‐(methoxymethoxy)benzene and 1‐(methoxymethoxy)‐3‐methoxybenzene were prepared by reported methods.…”

Section: Methodsmentioning

confidence: 99%

“…Elemental analyses were performed with a Perkin-Elmer 2400 series II CHN analyzer. (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G4), [10] 2,2′-bis(3-chloropyridin-2-yl)biphenyl, [9] 1-bromo-2-(methoxymethoxy)benzene [14] and 1-(methoxymethoxy)-3-methoxybenzene [15] were prepared by reported methods. Crystallography: A suitable crystal was mounted by using mineral oil on to a glass fiber and transferred to the goniometer of a Rigaku VariMax Saturn CCD diffractometer with graphite-monochromated Mo-Kα radiation (λ = 0.71070 Å).…”

Section: Methodsmentioning

confidence: 99%

Helical Folding of Hydroxy‐Substituted N‐Hetero‐ortho‐phenylenes Directed by Intramolecular Hydrogen Bonds

et al. 2017

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Derivatives of the ortho‐phenylene hexamer containing pyridine moieties and hydroxy groups were prepared through Negishi cross‐coupling reactions between bis(chloropyridyl)biphenyl and alkoxy‐substituted arylzinc reagents. X‐ray diffraction analysis revealed a closed helical folding directed by π–π stacking and hydrogen bonds. No broadening or coalescence of 1H NMR peaks was observed between 213 and 313 K, which indicates the high stability of the helical folding in CDCl3 solution. DFT calculations on the rotation of a single bond in the obtained compound indicated that the intramolecular hydrogen bonds led to exceptional stabilization of the closed helical folding. Right and left helices were separated by chiral column chromatography.

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“…Using the same strategy as described previously, 79 (À)-galanthamine was The aryl-sbustituted quaternary carbon certres 134, a key structural unit in the Amaryllidaceae alkaloids lycoramine and marididine 132, has been built via an ipso-nucleophilic addition of Na [Me 3 SiCH 2 CH 2 O 2 CCHCN] to the (1-arylcyclohexadienyl)organoiron electrophile 133. 81 A concise synthesis of unnatural (À)-homoganlanthamine 135 has been completed from m opioid antagonist naltrexone 136 in high total yield involving a Grob fragmentation of the corresponding N-chloroamine as the key step. 82 2.3.4 Phenanthridine alkaloids.…”

Section: Synthesismentioning

confidence: 99%