Acridone Alkaloids

Michael, Joseph P.

doi:10.1016/bs.alkal.2017.06.001

Cited by 14 publications

(13 citation statements)

References 223 publications

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“…The molecular skeleton of 9(10 H )-acridinone, first discovered from a natural alkaloid acronycine in 1948, is often observed in many bioactive natural products . It is composed of two benzene units linked by both a carbonyl and a secondary amino groups and adopts a planar conformation.…”

Section: Introductionmentioning

confidence: 99%

Investigation of Stepwise and Stoichiometric Palladium-Mediated ortho-C–H Bond Arylation and Alkylation of 9(10H)-Acridinone

Chu

Yen

et al. 2020

Organometallics

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We present a stoichiometric methodology for the synthesis of 4-arylated/alkylated 9(10H)-acridinones via a palladium-mediated ortho-C–H bond activation and C–C bond cross-coupling strategy. In the reaction, a N-(pyridin-2-yl)-9(10H)-acridinone palladacycle was employed as the starting substrate, which could be readily prepared by the stoichiometric reaction of N-(pyridin-2-yl)-9(10H)-acridinone and palladium(II) acetate in 89% isolated yield. Meanwhile, potassium aryl/alkyltrifluoroborates and p-benzoquinone were introduced to serve as the coupling partner and reaction promoter, respectively, in the presented palladium-mediated ortho-C–H bond arylation/alkylation of 9(10H)-acridinone. The reaction eventually furnished a variety of 4-arylated/alkylated 9(10H)-acridinones in 31–95% yields. The structures of N-(pyridin-2-yl)-9(10H)-acridinone palladacycle substrate and 4-phenylated/cyclopropylated 9(10H)-acridinone products were elucidated by X-ray crystallography. Kinetic isotope effect studies, as well as controlled experiments, were carried out to gain insight into the reaction mechanism. Finally, the removal of the directing group (i.e., pyridin-2-yl) was demonstrated on one of the ortho-arylated products, 4-phenyl-N-(pyridin-2-yl)-9(10H)-acridinone.

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Section: Introductionmentioning

confidence: 99%

Investigation of Stepwise and Stoichiometric Palladium-Mediated ortho-C–H Bond Arylation and Alkylation of 9(10H)-Acridinone

Chu

Yen

et al. 2020

Organometallics

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“…Among the various groups of small fluorescent molecules with large lifetimes, those based on the acridone moiety show fluorescence emission in the 400–500 nm region with lifetimes >10 ns, as well as pH independence in the physiological range (Smith et al, 2004 ). Approximately 270 alkaloids of the acridone family have been described (Michael, 2017 ), and due to their multiple uses, a large number of acridone derivatives have also been synthesized. Among their most noteworthy properties are the effects of acridones and synthetic analogs as antineoplastic agents (Kuete et al, 2015 ; Fomani et al, 2016 ; Schelz et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Coupled Excited-State Dynamics in N-Substituted 2-Methoxy-9-Acridones

et al. 2019

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Fluorophores of the acridone family have been widely employed in many applications, such as DNA sequencing, the detection of biomolecules, and the monitoring of enzymatic systems, as well as being the bases of intracellular sensors and even antitumoral agents. They have been widely used in fluorescence imaging due to their excellent photophysical properties, in terms of quantum yield and stability. However, frequently, the fluorescence emission data from acridones are not easily interpretable due to complex excited-state dynamics. The formation of π-stacking aggregates and excimers and excited-state proton transfer (ESPT) reactions usually result in emission features that are dependent on the experimental conditions. Therefore, an in-depth understanding of the dynamics involved in the excited-state transients of these dyes is mandatory for their appropriate application. Herein, we synthesized and fully characterized different 2-methoxy-9-acridone dyes. Their transient fluorescence emission spectra exhibited a complex dynamic behavior that can be linked to several excited-state reactions. We performed a thorough study of the excited-state dynamics of these dyes by means of time-resolved fluorimetry supported by computational calculations. All this allowed us to establish a multistate kinetic scheme, involving an ESPT reaction coupled to an excimer formation process. We have unraveled the rich dynamics behind this complex behavior, which provides a better understanding of the excited states of these dyes.

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“…Hypothetically, ANMT could also be an interesting candidate to produce the pharmaceutically interesting compounds O -propyl- or O -isopropyl- N -methylanthranilate [ 22 , 23 ]. In the biosynthesis of acridone alkaloids, e.g., in R. graveolens , N -methylation of anthranilate catalyzed by ANMT is a key step preceding CoA activation and, thus, separating primary metabolism (here tryptophan synthesis) from secondary metabolism [ 16 , 19 ]. Recently, production of about 26 mg·L −1 1,3-dihydroxy−10-methylacridone [ 65 ] and about 18 mg·L −1 4-hydroxy-1-methyl-2(1H)-quinolone [ 66 ] were established in E. coli coexpressing anmt from R. graveloens , anthranilate coenzyme A ligase from P. aeruginosa , and acridone synthase of R. graveolens or the anthraniloyl-CoA anthraniloyltransferase from P. aeruginosa .…”

Section: Discussionmentioning

confidence: 99%

“…Acridone alkaloids and avenacin are known as bioactive compounds with cytotoxic, anticancer, antimicrobial, or antiparasitic properties and are, therefore, used for pharmaceutical and therapeutic purposes. Several N -methylated acridones, namely citrusamine, evoxanthine, arborinine, or normelicopine, were identified in diverse plants [ 19 ]. Arborinine, as an example, was found in ethyl acetate extracts from Glycosmis parva, and it showed anticancer activity against human cervical cancer cells since activation of caspase-dependent apoptosis without inducing the DNA damage response was observed [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Fermentative N-Methylanthranilate Production by Engineered Corynebacterium glutamicum

et al. 2020

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The N-functionalized amino acid N-methylanthranilate is an important precursor for bioactive compounds such as anticancer acridone alkaloids, the antinociceptive alkaloid O-isopropyl N-methylanthranilate, the flavor compound O-methyl-N-methylanthranilate, and as a building block for peptide-based drugs. Current chemical and biocatalytic synthetic routes to N-alkylated amino acids are often unprofitable and restricted to low yields or high costs through cofactor regeneration systems. Amino acid fermentation processes using the Gram-positive bacterium Corynebacterium glutamicum are operated industrially at the million tons per annum scale. Fermentative processes using C. glutamicum for N-alkylated amino acids based on an imine reductase have been developed, while N-alkylation of the aromatic amino acid anthranilate with S-adenosyl methionine as methyl-donor has not been described for this bacterium. After metabolic engineering for enhanced supply of anthranilate by channeling carbon flux into the shikimate pathway, preventing by-product formation and enhancing sugar uptake, heterologous expression of the gene anmt encoding anthranilate N-methyltransferase from Ruta graveolens resulted in production of N-methylanthranilate (NMA), which accumulated in the culture medium. Increased SAM regeneration by coexpression of the homologous adenosylhomocysteinase gene sahH improved N-methylanthranilate production. In a test bioreactor culture, the metabolically engineered C. glutamicum C1* strain produced NMA to a final titer of 0.5 g·L−1 with a volumetric productivity of 0.01 g·L−1·h−1 and a yield of 4.8 mg·g−1 glucose.

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Acridone Alkaloids

Cited by 14 publications

References 223 publications

Investigation of Stepwise and Stoichiometric Palladium-Mediated ortho-C–H Bond Arylation and Alkylation of 9(10H)-Acridinone

Investigation of Stepwise and Stoichiometric Palladium-Mediated ortho-C–H Bond Arylation and Alkylation of 9(10H)-Acridinone

Coupled Excited-State Dynamics in N-Substituted 2-Methoxy-9-Acridones

Fermentative N-Methylanthranilate Production by Engineered Corynebacterium glutamicum

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