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Alkaloids from the Root of Isatis indigotica
Abstract
Seventeen new alkaloids (1-17) and 14 known analogues have been isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation, and electronic circular dichroism spectra calculations based on the quantum-mechanical time-dependent density functional theory. Compounds 1, 2, and 3 are the first examples of natural products with unique linkages between a molecule of 2-(4-methoxy-1H-indol-3-yl)acetonitrile and 2-(1H-indol-3-yl)acetonitrile, 2-(4-methoxy-1H-indol-3-yl)acetonitrile, and 4-hydroxyphenylethane, respectively. Compounds (-)-4 and (+)-4 represent the first natural products with the pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton. Some structural assignments for the new alkaloids suggest that the assignments made for certain previously reported alkaloids require revision. Compounds 1-3 and arvelexin (18) show antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2), with IC(50) values of 3.70-12.35 μM, and 17 inhibits Coxsackie virus B3 replication with an IC(50) of 6.87 μM.
... α-Arylacetonitriles are important structural motifs due to their extensive biological activities and are often found in natural products and commercial pharmaceuticals ( Figure 1). [1] For example, indole alkaloid 1, which was isolated from the root of Isatis indigotica by Shi and co-workers, [2] 12-epi-fischerindole W nitrile (2), isolated from the cultured cyanobacterium Fischella sp. by Orjala and co-workers, [3] anastrozole (3), an aromatase inhibitor used to treat breast cancer, [4] and verapamil (4), used as a calcium channel blocker in the treatment of angina, have one or more cyano groups at their benzylic positions. [5] In addition, arylacetonitriles are recognized as potentially valuable synthetic intermediates for well-known drugs such as ibuprofen as well as methadone since the cyano group can be readily converted into a wide variety of functional groups, such as amides, carboxylic acid derivatives, ketones, aldehydes, and amines, and it plays an important role in a number of α-CÀ H functionalizations of alkanenitriles. ...
... α-Arylacetonitriles are important structural motifs due to their extensive biological activities and are often found in natural products and commercial pharmaceuticals ( Figure 1). [1] For example, indole alkaloid 1, which was isolated from the root of Isatis indigotica by Shi and co-workers, [2] 12-epi-fischerindole W nitrile (2), isolated from the cultured cyanobacterium Fischella sp. by Orjala and co-workers, [3] anastrozole (3), an aromatase inhibitor used to treat breast cancer, [4] and verapamil (4), used as a calcium channel blocker in the treatment of angina, have one or more cyano groups at their benzylic positions. [5] In addition, arylacetonitriles are recognized as potentially valuable synthetic intermediates for well-known drugs such as ibuprofen as well as methadone since the cyano group can be readily converted into a wide variety of functional groups, such as amides, carboxylic acid derivatives, ketones, aldehydes, and amines, and it plays an important role in a number of α-CÀ H functionalizations of alkanenitriles. ...
A concise and direct Brønsted acid catalyzed cyanation of secondary and tertiary benzylic and allylic alcohols has been developed using trimethylsilyl cyanide (TMSCN) as a cyanide source and 1,1,1,3,3,3‐hexafluoro‐2‐propanol (HFIP) as a solvent. The present transition‐metal‐free catalytic process is operationally simple to perform under “open‐flask” conditions and is applicable to the preparation of a number of α‐arylacetonitriles as well as late‐stage material transformations. The effectiveness of the present protocol was further demonstrated by the first enantioselective synthesis and determination of the absolute configuration of verimol F.
While natural products have undoubtedly played a pivotal role in drug discovery, their potential as lead compounds has been hindered by challenges such as limited accessibility and complex synthesis processes. At the core of numerous natural and synthetic compounds, each exhibiting remarkable biological traits, lies the foundational structure of 3,4-dihydro-2(1H)-quinolinone, also known as 2-oxo-tetrahydroquinoline (2 O-THQ). This article extensively examines the occurrence of 2 O-THQ alkaloids across the plant kingdom, exploring their capacity to serve as a source for innovative bioactive natural products. Despite the undeniable significance of these compounds, the existing body of review literature has yet to provide comprehensive coverage, underscoring the pivotal contribution of this present article in investigating their prevalence in nature.
Epoxides are oxygen containing heterocycles which are significantly employed as crucial intermediates in various organic transformations. They are considered highly reactive three-membered heterocycles due to ring strain and they undergo epoxide ring opening reactions with diverse range of nucleophiles. Epoxide ring-opening reactions have gained prominence as flexible and effective means to obtain various functionalized molecules. These reactions have garnered substantial attention in organic synthesis, driven by the need to comprehend the synthesis of biologically and structurally important organic compounds. They have also found applications in the synthesis of complex natural products. In this review article, we have summarized the implementation of epoxide ring opening reactions in the synthesis of alkaloids and terpenoids based natural products reported within the last decade (2014-2023).
An electrooxidative reconstruction of the indole core under ambient conditions is reported, resulting in the construction of tryptanthrins. This electrochemical strategy simplifies molecular skeleton‐hopping by employing commercially available NH‐indole feedstock as the starting materials. Furthermore, the synthetic value of this skeletal reconstruction was demonstrated by divergent further transformations. A preliminary mechanistic investigation involving control experiments and cyclovoltammetric studies showed the indispensability of electricity, as well as the importance of oxygen and TEMPO, thereby revealing a possible reaction pathway.
The JAK-STAT pathway plays a crucial role in the signaling cascade associated with various cytokines that have been implicated in the pathogenesis of inflammatory diseases and myeloproliferative neoplasms (MPN). Among the isoforms of JAKs, the JAK2 subtype is primarily responsible for the function of hematopoietic system cells, making it a significant target in the treatment of MPN. However, the precise regulatory role of JAK2 in inflammatory diseases requires further investigation and confirmation. The current study employed a selective JAK2 inhibitor, ZT55, derived from Isatis indigotica roots, to examine its regulatory effects on inflammatory and immune responses in delayed-type hypersensitivity (DTH) and arthritis in mice. To evaluate the efficacy of ZT55 treatment, DNFB-induced DTH and collagen-induced arthritis (CIA) mouse models were utilized. T cells were cultured and subsequently analyzed for proliferation and activation using flow cytometry and EdU assay. Additionally, the maturation and function of dendritic cells were assessed through flow cytometry and ELISA. Our findings indicate that ZT55 significantly reduced DNFB-induced DTH and attenuated inflammation, cartilage degradation, and bone destruction in CIA mice. Moreover, ZT55 was found to inhibit the proliferation and activation of T cells and the maturation of dendritic cells by regulating the JAK2-STAT3 signaling pathway. These results suggest that selectively targeting the JAK2 isoform could have anti-inflammatory and immunosuppressive effects by regulating the adaptive and innate immune responses via the JAK2-STAT3 signaling pathway. Therefore, ZT55 has the potential to be a promising pharmaceutical candidate for the treatment of inflammatory and autoimmune diseases.
A E-2-[(3'-indole)cyanomethylene]-3-indolinone was isolated from the root of Isatis indigotica Fort. The structure elucidation and 1 H, 13 C NMR assignments were achieved by spectroscopic method. Keywords: Isatis indigotica Fort., E-2-[(3'-indole)cyanomethylene]-3-indolinone. Isatis indigotica Fort., a most popular Chinese traditional medicine, is usually used to clear heat and detoxicate. We report here the isolation of E-2-[(3'-indole)cyanomethylene]-3-indolinone 1 (Scheme) from the butanol-soluble fraction of I. indigotica., and structural elucidation of this new alkaloid.
From the roots of Isatis indigotica, two new alkaloids named isaindigotidione 1 and isaindigotone 2 were isolated. Their structures were elucidated by spectral and X-ray crystallographic analyses. 1 is the first discovered indolizino[7,6-c]quinoline derivative.
Brassicanal C, a new sulphur-containing phytoalexin, and two dioxindoles were isolated from cabbage inoculated with Pseudomonas cichorii. Brassicanal C was shown to possess a unique sulphinate structure on the basis of spectroscopic data and optical activity. One of the dioxindoles, dioxibrassinin, appears structurally to be a possible precursor to spirobrassinin.
Nitrile hydratase, that is produced abundantly in cells of J1, catalyses the conversion of various aromatic nitrile derivatives to the corresponding amides. Using J1 resting cells, the conditions for the production of benzamide, 2,6-difluorobenzamide, indoleacetamide, thiophenecarboxamide and furanecarboxamide here optimized. Under the determined conditions, 489 g of benzamide, 306 g of 2,6-difluorobenzamide, 1045 g of 3-indoleacetamide, 210 g of 2-thiophenecarboxamide and 522 g of 2-furanecarboxamide were produced, with 100% molar conversion, from the corresponding nitriles, per litre of reaction mixture.
The synthesis of enantiomerically pure (R)-2-methyl-3-oxo-perhydro-1,4-oxazine is described for the first time. Stereochemical proofs are given and the formation of byproducts is discussed.
Five glycosides were isolated from the leaves of Celosia argentea L. and their structures were determined based on UV, MS, 1H NMR and 13C NMR spectroscopic data as 1-(4-O-β-glucopyranosyl-3-methoxyphenyl) propane-2-ene (citrusin C, 1), 3-O-β-glucopyranosyl-1H-indole (indican, 2), (3Z)-hexenyl-(1-O-α-rhamnopyranosyl-β-glucopyranoside) (3), (3Z)-hexenyl-1-O-β-glucopyranoside (4), and (7E)-6,9-dihydromegastigma-7-ene-3-one-9-O-[β-glucopyranoside (5). On bioassay on the germination of lettuce, compound 1, the aglycone of 1 (1a), and the aglycone of 3 (3a) exhibited growth inhibitory activity, whereas compound 2 and 3 exhibited growth promotive activity. Compounds 1–5 were detected in the leaves of Celosia argentea L. for the first time in this study.
A new indole alkaloid 1, together with four known indole alkaloids 2–5, was isolated from the 95% EtOH extract of the traditional Chinese medicinal plant Isatis indigotica. Alkaloids 2–5 were found in the plant for the first time. Their structures were elucidated as 3-hydroxy-3-acetonitrile-4-hydroxy-2-indolone
(1), 1-methoxy-3-indoleacetonitrile (2), 3-indoleacetic acid (3), 3-indolealdehyde (4), and 1-methoxy-3indolecarbaldehyde (5) on the basis of spectroscopic data. Their anti-HSV effects in vitro were evaluated by plaque reduction assay.
Syntheses of derivatives of three novel indole-fused systems based on indolo[2,1-d][1,5]benzodiazocine, indolo[7,7a,1-d,e][1,6]benzodiazonine and pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline, the first two including 8- and 9-membered ring heterocycles, are described. These derivatives resulted from the photo-induced cyclization of the respective chloroacetamide precursors prepared via N-alkylation of the appropriate indole with 2-nitrobenzyl bromide, subsequent nitro group reduction and then N-chloroacetylation. Structural and stereochemical features of these new ring system derivatives are discussed.