Carbazole Alkaloids Research Articles

Identification of Carbazole Alkaloid Derivatives with Acylhydrazone as Novel Anti-TMV Agents with the Guidance of a Digital Fluorescence Visual Screening.

Difficulty in preventing crops from plant viruses urges to discover novel efficient antiviral chemicals, which is sped up by precise screening methods. Fluorescence-based methods have recently been applied as innovative and rapid tools for visually monitoring the replication of viruses and screening of antivirals, whereas the quantification of fluorescence signals mainly depends on manually calculating the fluorescent spots, which is time-consuming and imprecise. In the present work, the fluorescence spots were automatically identified, and the fluorescence area was directly quantified by a program developed in our group, which avoided subjective errors from the operators. We further employed this digital and visual screening assay to identify antivirals using the tobacco mosaic virus-green fluorescence protein (TMV-GFP) construct, in which the expression of GFP intuitively reflected the efficacy of antivirals. The accuracy of this assay was validated by quantifying the activities of the commercial antiviral inhibitors ribavirin and ningnanmycin and then was applied to evaluate the subtle activity differences of a series of newly synthesized carbazole and β-carboline alkaloid derivatives. Among them, compounds 5 (76%) and 11 (63%) exhibited anti-TMV activities comparable to that of ningnanmycin (65%) at 50 μM, and they delayed the multiplication of TMV in the early stage of infection without phytotoxicity. Taken together, these findings demonstrated that the digital and visual TMV-GFP screening method was competent to test the antiviral activities of compounds with subtle modifications and facilitated the discovery of novel antivirals.

Carbazole alkaloids with potential cytotoxic activities targeted on PCK2 protein from Murraya microphylla

From the 95% aqueous ethanol extract of Murraya microphylla, five pairs of new carbazole alkaloid enantiomers, (+/–)-microphylines N–R (1a/1b–5a/5b), were isolated, together with 20 known carbazole alkaloids. The structures of the new compounds were determined by the HRMS and NMR spectroscopic data, along with the calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. The known compound (+)-mahanine (21) showed significant cytotoxicities against Du145, HepG2, HeLa, and HCT-116 cell lines, and its possible mechanism was deduced to target on phosphoenolpyruvate carboxykinase 2 (PCK2) protein via surface plasmon resonance (SPR) and molecular docking.

Selective and effective anticancer agents: Synthesis, biological evaluation and structure–activity relationships of novel carbazole derivatives

Carbazole alkaloids is an important class of natural products with diverse biological functions. So, the aim of this article is to explore new chemical entities containing carbazole scaffold as potential novel cytotoxic agents based on our developed three-component indole-to-carbazole reaction. Two series of carbazole derivatives were designed and synthesized, and their in vitro cytotoxic activities against three cell lines (A875, HepG2, and MARC145) were evaluated. The results indicated that some of these carbazole derivatives exhibited significantly good cytotoxic activities against tested cell lines compared with the control 5-fluorouracil (5-FU). Especially, carbazole acylhydrazone compounds 7g and 7p displayed high inhibitory activity on cancer cells, but almost no activity on normal cells. Further analysis of induced apoptosis for potential compounds indicated that the potential antitumor agents induced cell death in A875 cells at least partly (initially) by apoptosis, which might be used as promising lead scaffold for discovery of novel carbazole-type cytotoxic agents.

A Simple BF3•Et2O-mediated Cycloaddition Reaction to the Formation of Cyclic Monoterpenoid Pyrano[3,2-a]carbazole Alkaloids

Abstract: A Lewis acid BF3•Et2O-mediated intramolecular cycloaddition reaction of mahanimbine (1) is described. Three cycloadducts, bicyclomahanimbine (2), cyclomahanimbine (3) and murrayazolinine (4) were obtained. The structural characterization of these compounds was determined by 1D and 2D NMR experiments. These compounds showed no cytotoxic activity against human MRC-5 cells (IC50 > 60 μg/mL). Compound 3 showed the highest inhibition cytotoxic effects against HeLa and HL-60 cancer cells with IC50 values of 10.0 and 28.7 μg/mL, respectively. This strategy opens a new approach for the synthesis of biologically significant cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids.

Cover Picture

The cover picture shows four new chlorinated carbazole alkaloids, chlocarbazomycins (CCBs) A—D isolated from sponge associated bacterium Streptomyces diacarni LHW51701. Their structures were elucidated via spectroscopic techniques (including HRESIMS, 1D & 2D NMR), and X‐ray crystallographic analysis. More details are discussed in the article by Lin on page 1188—1192.image

Divergent Total Synthesis of (±)‐Mahanine and Other Carbazole Alkaloids

AbstractWe represent here, a divergent approach for the total synthesis of (±)‐Mahanine and twelve other naturally occurring carbazole alkaloids. Remarkably, we have utilized a simplified scalable Suzuki coupling for C−C bond formation and a metal‐free C−N coupling sequence to synthesize the functionalized carbazole scaffold from a single intermediate. Subsequently, either functional group manipulations or late‐stage pyran ring annulation furnished a library of 13 carbazole alkaloids mostly isolated from a traditional medicinal plant Murraya koenigii. The construction of carbazole moiety at the initial‐stage followed by late‐stage pyran annulation under mild condition overcomes the decomposition problem of pyran‐ring under acidic or other harsh reaction conditions.

Antimicrobial Chlorinated Carbazole Alkaloids from the Sponge‐Associated Actinomycete Streptomyces diacarniLHW51701

Main observation and conclusionFour new chlorinated carbazole alkaloids, chlocarbazomycins (CCBs) A—D, were isolated from sponge associated bacterium Streptomyces diacarni LHW51701. Their structures were elucidated via spectroscopic techniques (including HRESIMS, 1D & 2D NMR), and X‐ray crystallographic analysis. Structurally, the 4‐chloro coupled with 3‐methoxyl substituents in the tricycle nucleus of CCBs A—D and the N‐methoxyl group of CCB‐D are rare in naturally occurred tricyclic carbazole alkaloids. Moreover, CCBs A—D do not bear the typical C1 para‐alkyl and C2 meta‐methyl side chains of bacterial tricycle carbazoles, suggesting a novel mechanism of aromatic ring formation in biosynthesis. The biological evaluation showed that CCB‐C possessed inhibitory activities against pathogenic microorganisms including methicillin‐resistant Staphylococcus aureus (MRSA), Mycobacterium smegmatis, Bacillus mycoides, and Candida albicans.

Phytochemistry, pharmacology and botanical aspects of Murraya Koenigii in the search for molecules with bioactive potential - A review

The magical plant of Indian spice, Murraya koenigii(curry leaf) family Rutaceae grows throughout the Indian subcontinent. It is used in the treatment or prevention of many diseases including kidney stone, dysentery disorders, renal pain, stomach upsets & morning sickness. It is one of the main components of formulation in the traditional ayurvedic system of medicine since many centuaries. A scrutiny of literature reveals some notable pharmacological activities of plant. These include pharmacological activities such as antioxidant, antidiabetic, antitumor and neuroprotective.The leaves, roots and barks of this plant are rich in source of carbazole alkaloids. The carbazole alkaloids includes koenigin, bicyclomahanim-bicine, cyclomahanimbine, murrayastine, coumarine, koenidine has medicinal activities.

Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53.

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

Enantioselective Alkoxycyclization of 1,6-Enynes with Gold(I)-Cavitands: Total Synthesis of Mafaicheenamine C.

Chiral gold(I)‐cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6‐enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)‐mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio‐ and stereoselectivities.

Enantioselective Alkoxycyclization of 1,6‐Enynes with Gold(I)‐Cavitands: Total Synthesis of Mafaicheenamine C

AbstractChiral gold(I)‐cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6‐enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)‐mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio‐ and stereoselectivities.

Carbazole alkaloids from the fruits of Clausena anisum-olens with potential PTP1B and α-glucosidase inhibitory activities

The phytochemical investigation on the fruits of Clausena anisum-olens led to the isolation of 18 carbazole alkaloids (1–18), containing three new ones, clausenanisines A–C (1–3), and three new naturally occurring carbazole alkaloids, clausenanisines D–F (4–6), as well as 12 known analogues (7–18). The chemical structures of clausenanisines A–F (1–6) were elucidated by extensive spectroscopic methods. Notably, clausenanisine A (1) was a novel carbazole alkaloid with a unique five-membered cyclic ether, while clausenanisine E (5) is an unusual carbazole alkaloid owning an unprecedented naturally occurring carbon skeleton possessing 14 carbon atoms. The known carbazole alkaloids (7–18) were identified by the comparison of their spectral data with those data reported in the literature. All known carbazole alkaloids 7–18 were isolated from C. anisum-olens for the first time. Moreover, all isolated compounds 1–18 were assessed for their protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitory activities in vitro. Compounds 1–18 exhibited remarkable PTP1B inhibitory activities with IC50 values in the range of 0.58 ± 0.05 to 38.48 ± 0.32 μM, meanwhile, compounds 1–18 displayed significant α-glucosidase inhibitory activities with IC50 values ranging from 3.28 ± 0.16 to 192.23 ± 0.78 μM. These research results imply that the separation and identification of these carbazole alkaloids showing notable PTP1B and α-glucosidase inhibitory activities from the fruits of C. anisum-olens can be very significant for discovering and developing new PTP1B inhibitors and α-glucosidase inhibitors for the treatment of diabetes mellitus.

In silico Molecular Docking, DFT Analysis and ADMET Studies of Carbazole Alkaloid and Coumarins from Roots of Clausena anisata: A Potent Inhibitor for Quorum Sensing.

IntroductionIn modern drug design, in silico methods are largely used to understand drug-receptor interactions and quantum chemical properties. In the present study, a computational de novo design approach was used to confirm mode of binding for antibacterial activity, elucidating quantum chemical properties and ADMET-drug-likeness of carbazole alkaloid (1) and three coumarins (2–4) isolated from roots of Clausena anisata.MethodsDocking studies were performed with DNA-Gyrase (6F86) and LasR binding domain (2UV0) employing a flexible ligand docking approach using AutoDock Vina. SwissADME prediction and toxicological predictions were performed by ADMET. The optimized structures and molecular electrostatic potential surface of the isolated compounds were predicted by DFT analysis using B3LYP/6-31G basis levels.Results and DiscussionThe docking results revealed that compound 3 showed better docking scores against both DNA gyrase B and LasR binding domain compared with ciprofloxacin with potential as an inhibitor of bacterial DNA gyrase and quorum sensing LasR binding domain. The SwissADME prediction results showed that all the isolated compounds (1–4) satisfy Lipinski’s rule of five with zero violations. Toxicological prediction results suggested that all compounds and ciprofloxacin are non-hepatotoxic, non-carcinogenic, non-irritant, immunogenic, and non-cytotoxic. The DFT analysis results revealed that compound 3 has large electronegativity (χeV), global softness (σ eV−1), global electrophilicity (ωeV), and mutagenicity value closer to ciprofloxacin (with LD50 value of 480 mg/kg) suggesting better bioactivity and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups.ConclusionOverall, compound 3 may serve as a lead molecule that could be developed into a potent E. coli DNA gyrase B inhibitor and efficient inhibitor for quorum sensing auto-inducer LasR binding domain of Pseudomonas aeruginosa.

Heptaphylline inhibits the proliferation and epithelial to mesenchymal transition of human pancreatic cancer cells via induction of apoptosis and autophagy

Heptaphylline, a carbazole alkaloid, has been shown to exert anticancer effects against different human cancers. The study was designed to evaluate the anticancer effects of heptaphylline against the human pancreatic cancer cell and to explore the underlying mechanism. The results showed that heptaphylline inhibited the proliferation of all the pancreatic cancer cell lines with lowest IC50 of 12 µM against the PANC1 cells. In contrary, the IC50 of heptaphylline was around eight times higher against the normal H6c7 cells. The transwell assays revealed heptaphylline inhibited the migration and invasion of pancreatic cancer cells in a concentration-dependent manner. Additionally, the epithelial to mesenchymal transition of the PANC1 cells was also inhibited upon treatment with heptaphylline. The antiproliferative effects of heptaphylline were exerted via induction of apoptosis in pancreatic cancer cells. The apoptosis was associated with an increase in Bax, decrease in Bcl-2 expression, discharge of cytochrome c and cleavage of PARP, caspase-3 and caspase-9. AO staining revealed that heptaphylline induced autophagy in PANC1 cancer cells by increasing the expression of LC3B-II and Beclin-1. Taken together, heptaphylline suppresses the growth of pancreatic cancer via induction of apoptosis and autophagy and may prove a potent lead molecule for the development of chemotherapy.

Ring closing metathesis for the construction of carbazole and indole-fused natural products.

The synthesis and functionalization of carbazole ring systems have received considerable attention in organic synthesis due to their widespread occurrence in biologically active compounds. One of the classical methods for the synthesis of carbazoles involves C-C bond formation of a biaryl amine moiety by oxidizing agents. Over the last few years, various new strategies have evolved for the synthesis of carbazole ring systems. During the past two decades, ring-closing metathesis (RCM) based approaches have been efficiently employed for the synthesis of nitrogen containing heteroaromatic systems including carbazoles. Herein, we discuss the construction of carbazole ring systems using RCM and the application of RCM based methods in the preparation of other indole-fused heterocycles. The application of these methods in the synthesis of carbazole alkaloids and bioactive indole-fused natural products has been discussed to highlight the importance of RCM in total synthesis.

Rhodium-Catalyzed Crossed [2+2+2] Cycloaddition with Ynamides: Key-Strategy for the Concise Total Synthesis of 3-Oxygenated Carbazole Alkaloids

Rhodium-Catalyzed Crossed [2+2+2] Cycloaddition with Ynamides: Key-Strategy for the Concise Total Synthesis of 3-Oxygenated Carbazole Alkaloids

Synthesis and biological evaluation of pyranocarbazole derivatives as Anti-tumor agents

A series of pyrano[3,2-a]carbazole alkaloids were designed and synthesized as derivatives of Girinimbine. The anticancer activities of these derivatives (3, 4a-j, 5a, 5c, 5f, 5i, 6c, 7a, 7c, 7f, 7i) against 10 cancer cell lines were studied. Among them, compounds 3 and 7i with N-methyl piperazine showed significant anticancer activity against MCF-7 cell lines with the IC50 values of 1.77 and 4.32 μM, respectively. Furthermore, their effects on altering cell morphology, inducing cell cycle arrest and apoptosis in MCF-7 cells were studied in vitro. In addition, the molecular docking study was carried out by using Discovery Studio software to predict the interactions between these derivatives and tubulin. All in all, these consequences reveal that pyranocarbazole derivatives with N-methyl piperazine can be used as potential anticancer lead compounds and provide useful points for the further optimization of pyranocarbazole alkaloids.

A highly efficient methodology for the preparation of N-methoxycarbazoles and the total synthesis of 3,3′-[oxybis(methylene)]bis(9-methoxy-9H-carbazole)

A convenient and highly efficient method is described for the synthesis of N-methoxycarbazole derivatives, including those with sterically demanding, benzannulated, or strongly electron-donating or -withdrawing substituents. Various N-methoxycarbazole derivatives were directly prepared in good-to-moderate yields by the Pd2(dba)3CHCl3/9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene-catalyzed reactions of the corresponding dibromobiphenyl compounds and methoxyamine. Based on this methodology, the first total synthesis of 3,3′-[oxybis(methylene)]bis(9-methoxy-9H-carbazole), an antimicrobial dimeric carbazole alkaloid previously isolated from the stem bark of Murraya koenigii, was achieved in 18% yield over seven steps from 1,2-dibromobenzene.

First Total Synthesis and Investigation of the X-ray Crystal Structure of the Pyrano[3,2-a]carbazole Alkaloid Clausenalansine A

AbstractWe describe the first total synthesis of the recently discovered pyrano[3,2-a]carbazole alkaloid clausenalansine A. The synthetic strategy for the construction of this formylpyrano[3,2-a]carbazole is based on a sequence of Buchwald–Hartwig coupling, palladium(II)-catalyzed oxidative cyclization, Lewis acid promoted annulation of the pyran ring, and chemoselective oxidation of a methyl to a formyl group.

Nitric Oxide Inhibitory Carbazole Alkaloids from the Folk Medicine Murraya tetramera C.C. Huang.

The phytochemical investigation of the leaves and stems of Murraya tetramera C.C. Huang, a traditional folk medicine used as an anti-inflammatory agent, yielded 19 simple carbazole alkaloids, two of which (1-ethoxy-3-methyl-9H-carbazol-2-ol (1) and 7-hydroxy-2,8-dimethoxy-6-methyl-9H-carbazole-1-carbaldehyde (2)) are new ones. The structures of the new compounds were determined by extensive spectroscopic analysis including NMR and HR-EI-MS experiments, as well as comparison with the reported data. Most of the isolates showed potent inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells with IC50 values ranging from 5.1 to 15.1 μM.