Quinoline Alkaloids Research Articles

A simple and specific quantitative method for determination of dictamnine in Dictamni Cortex by 1H NMR spectroscopy

Dictamni Cortex (Baixianpi) is a commonly used medicinal herb in traditional Chinese medicines (TCMs), possessing various bioactivities. Quinoline alkaloids are regarded as one of the main active components in this herb. In the present study, a more convenient, specific and accurate analytical method using 1H NMR has been developed for the quantitative determination of dictamnine, one of the main active quinoline alkaloids in Dictamni Cortex. In a less crowded region δ 8.0–8.5, the signal of H-5 of dictamnine was well separated from other signals in chloroform-d1. The quantity of dictamnine was calculated by means of the integral value of H-5 of dictamnine to that of the known amount of internal standard, pyrazine. This assay was precise and reproducible, with RSDs less than 3%. The recovery results of dictamnine were observed between 92.10 and 108.10% and the limit of detection (LOD) and limit of quantitation (LOQ) were 3.3 μg ml−1 and 13.2 μg ml−1, respectively. This newly developed method was proven to be highly accurate, precise and robust, for the determination of dictamnine in Dictamni Cortex. The results obtained from 1H NMR method were also compared with those from conventional HPLC method, and no remarkable difference was found between these two methods.

Biomimetic Synthesis and Biological Evaluation of Aplidiopsamine A

The first total synthesis of Aplidiopsamine A, a rare 3H-pyrrolo[2,3-c]quinoline alkaloid from the Aplidiopsis confluata, has been achieved following the proposed biosynthesis. This biomimetic synthesis requires only five steps and proceeds in 20.8% overall yield. Biological evaluation across large panels of discrete molecular targets identified that Aplidiopsamine A is a highly selective PDE4 inhibitor, a target for numerous CNS disorders.

Studies on the chemical constituents of Evodia rutaecarpa and Evodia rutaecarpa passed with Liquorice and biological activities

17 indole quinoline alkaloids, 8 limonins, 7 flavonoids, 7 triterpenoids and 11 other compounds were obtained from E. rutaecarpa and E. rutaecarpa passed with Liquorice. 6 of them are new compounds. About 19 compounds were tested by replanting tumor to mice, angioma of zebrafish model for antiangiogenic drug screening and human tumor cells in vitro. Thus compounds evodiagenine (2), evodialimonin (3), rhetsinine (4), dehydroevodiamine (5), wuchuyuamide I (7) and 1-methyl-2-undecyl-4(1H)-quinolone (8) showed moderate activity against human tumor cells, dievodiamine (1) and evodiamine (6) showed good activity. The inhibitory rate of 4 on sarcoma S180 was 57.78% at the dose of 5–10mg/kg·d in vivo. Moreover, the inhibition of the active selectivity of cycloxygenase 1 and 4 showed a stronger effect.

Fitoquímica e quimiossistemática de Conchocarpus marginatus e C. inopinatus (Rutaceae)

Phytochemical studies of the leaves and stem have led to the identification of the known acridone alkaloids arborinine, methyl-arborinine, 1-hydroxy-3-methoxy-N-methyl acridone, xanthoxoline, 1,2,3,5-tetramethoxy-N-methylacridone, toddaliopsin C and the new seco acridone alkaloid inopinatin. The known quinoline alkaloids 2-phenyl-1-methyl-quinolin-4(1H)-one, 2-phenyl-1-methyl-7-methoxy-quinolin-4(1H)-one, dictamnine, and the coumarins scopoletin and marmesin were also isolated. The isolated compounds and the distribution of secondary metabolites, which are systematically important, obtained from literature, clearly confirmed that some species formerly described in the genera Angostura and Galipea in fact shall belong to the genus Conchocarpus.

Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents

Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion.

ChemInform Abstract: seco‐Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity.

AbstractThe novel seco‐limonoid raputiolide (I) and the new quinoline alkaloids heptaphyllone A (II) and B (III) are isolated together with six known compounds.

Rapid and Green Analytical Method for the Determination of Quinoline Alkaloids from Cinchona succirubra Based on Microwave-Integrated Extraction and Leaching (MIEL) Prior to High Performance Liquid Chromatography

Quinas contains several compounds, such as quinoline alkaloids, principally quinine, quinidine, cinchonine and cichonidine. Identified from barks of Cinchona, quinine is still commonly used to treat human malaria. Microwave-Integrated Extraction and Leaching (MIEL) is proposed for the extraction of quinoline alkaloids from bark of Cinchona succirubra. The process is performed in four steps, which ensures complete, rapid and accurate extraction of the samples. Optimal conditions for extraction were obtained using a response surface methodology reached from a central composite design. The MIEL extraction has been compared with a conventional technique soxhlet extraction. The extracts of quinoline alkaloids from C. succirubra obtained by these two different methods were compared by HPLC. The extracts obtained by MIEL in 32 min were quantitatively (yield) and qualitatively (quinine, quinidine, cinchonine, cinchonidine) similar to those obtained by conventional Soxhlet extraction in 3 hours. MIEL is a green technology that serves as a good alternative for the extraction of Cinchona alkaloids.

Iridoid-specific Glucosyltransferase from Gardenia jasminoides

Iridoids are one of the most widely distributed secondary metabolites in higher plants. They are pharmacologically active principles in various medicinal plants and key intermediates in the biosynthesis of monoterpenoid indole alkaloids as well as quinoline alkaloids. Although most iridoids are present as 1-O-glucosides, the glucosylation step in the biosynthetic pathway has remained obscure. We isolated a cDNA coding for UDP-glucose:iridoid glucosyltransferase (UGT85A24) from Gardenia jasminoides. UGT85A24 preferentially glucosylated the 1-O-hydroxyl group of 7-deoxyloganetin and genipin but exhibited only weak activity toward loganetin and no activity toward 7-deoxyloganetic acid. This suggests that, in the biosynthetic pathway of geniposide, a major iridoid compound in G. jasminoides, glucosylation occurs after methylation of 7-deoxyloganetic acid. UGT85A24 showed negligible activity toward any acceptor substrates other than iridoid aglycones. Thus, UGT85A24 has a remarkable specificity for iridoid aglycones. The mRNA level of UGT85A24 overlaps with the marked increase in genipin glucosylation activity in the methyl jasmonate-treated cell cultures of G. jasminoides and is related to iridoid accumulation in G. jasminoides fruits.

Inhibitory alkaloids from Dictamnus dasycarpus root barks on lipopolysaccharide-induced nitric oxide production in BV2 cells

The methanolic extract of Dictamnus dasycarpus root barks afforded one new glycosidic quinoline alkaloid, 3-[1β-hydroxy-2-(β-D-glucopyranosyloxy)-ethyl)-4-methoxy-2(1H)-quinolinone (1), together with nine known compounds, preskimmianine (2), 8-methoxy-N-methylflindersine (3), dictamine (4), γ-fagarine (5), halopine (6), skimmianine (7), dictangustine-A (8), iso-γ-fagarine (9), isomaculosidine (10). The isolated alkaloids significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 cells. Among them, compounds 3 and 7 showed the most potent inhibitory activities on LPS-induced NO production.

Novel indole and quinoline alkaloids from Melodinus yunnanensis

6/7-Seco rearranged spiro-indolone alkaloids, meloyunines A (1) and B (2) and a monoterpenoid quinoline alkaloid meloyunine C (3) together with its possible intermediate 14,15-dehydromelohenine B (4), and their precursor Δ14-vincamenine (5) were isolated from Melodinus yunnanensis. All structures were elucidated based on NMR, FTIR, UV, and MS spectroscopic data. The isolation of monoterpenoid indole, quinoline, and its immediate from the same plant chemically supported the biosynthesis of quinoline from indole. Compound 2 was cytotoxic against several human cancer cell lines. Electronic Supplementary MaterialSupplementary material is available for this article at 10.1007/s13659-011-0001-0 and is accessible for authorized users.

Unprecedented Anthranilate Priming Involving Two Enzymes of the Acyl Adenylating Superfamily in Aurachin Biosynthesis

Biosynthesis of many polyketide-derived secondary metabolites is initiated by incorporating starter units other than acetate. Thus, understanding their priming mechanism is of importance for metabolic engineering. Insight into the loading process of anthranilate into the biosynthetic pathway for the quinoline alkaloids aurachins has been provided by the sequencing of a partial biosynthetic gene cluster in the myxobacterium Stigmatella aurantiaca. The cluster encodes a predicted aryl:CoA ligase AuaE that was hypothesized to activate and transfer anthranilate to the acyl carrier protein AuaB. However, gene inactivation and in vitro experiments described here contradicted this model. Aided by the genome sequence of S. aurantiaca, we identified an additional aryl:CoA ligase homologue, AuaEII, encoded in a different gene operon, which is additionally required for anthranilate priming. We report the characterization of both enzymes and the elucidation of a novel non-acetate priming strategy in thio-templated biosynthetic machineries.

AuaA, a Membrane‐Bound Farnesyltransferase from Stigmatella aurantiaca, Catalyzes the Prenylation of 2‐Methyl‐4‐hydroxyquinoline in the Biosynthesis of Aurachins

Aurachins are quinoline alkaloids isolated from the myxobacterium Stigmatella aurantiaca. They are substituted with an isoprenoid side chain and act as potent inhibitors in the electron transport chain. A biosynthetic gene cluster that contains at least five genes (auaA-auaE) has been identified for aurachin biosynthesis. In this study, auaA, the gene encoding a putative prenyltransferase of 326 amino acids, was cloned and overexpressed in Escherichia coli. Biochemical investigations showed that AuaA catalyzes the prenylation of 2-methyl-4-hydroxyquinoline in the presence of farnesyl diphosphate (FPP), thereby resulting in the formation of aurachin D. The hydroxyl group at position C4 of the quinoline ring is essential for an acceptance by AuaA; this was concluded by testing 18 quinoline derivatives or analogues with AuaA and FPP. (1) H NMR and HR-EI-MS analyses of six isolated enzyme products revealed the presence of a farnesyl moiety at position C3 of the quinoline ring. K(M) values of 43 and 270 μM were determined for FPP and 2-methyl-4-hydroxyquinoline, respectively. Like other known membrane-bound prenyltransferases, the reaction catalyzed by AuaA is dependent on the presence of metal ions such as Mg(2+) , Mn(2+) and Co(2+) , although no typical (N/D)DXXD binding motif was found in the sequence.

Insight into the Mechanism of Quinoline Formation by the Chromium(0) Fischer Carbene Catalytic Transmetallation to Palladium and Rhodium: Application to the Synthesis of the Alkaloids of Ruta chalepensis

AbstractThe Pd‐ and Rh‐mediated cyclization of group 6 (2‐aminoethenyl)carbene complexes incorporating aryl iodides or boronates in their structures is reported. The process led to the formation of quinoline rings and has been applied to the synthesis of quinoline alkaloids 12 and 13 isolated from the roots of the perennial grass Ruta chalepensis. The computational (DFT) study of the cyclization processes revealed unusual features. Thus, for the Pd‐mediated cyclization of (2‐aminoethenyl)carbene complexes incorporating aryl iodides in their structures, the first step in the pathway to the quinolines is the Cr‐to‐Pd transmetallation reaction, leading to palladacarbenes instead of the expected oxidative addition to the aryl iodide. For RhI‐mediated cyclizations in (2‐aminoethenyl)carbene complexes incorporating aryl boronates, the sequence of events involves an initial Cr‐to‐Rh transmetallation followed by oxidative addition to the aryl–boron bond. The evolution of these intermediates to the final quinolines parallels the Pd‐catalyzed pathway.

Pharmacological properties of pteleprenine, a quinoline alkaloid extracted from Orixa japonica, on guinea-pig ileum and canine left atrium.

We have investigated the pharmacological properties of pteleprenine, a quinoline alkaloid, on contractile responses of the guinea-pig ileum and on inotropic responses of the canine left atrium. Although pteleprenine (0.1-1 microM) had no effect on the contraction of the ileum induced by acetylcholine at 10 microM it significantly inhibited acetylcholine-induced contraction of the ileum. Pteleprenine (0.1-10 microM) reduced nicotine induced-contraction of the ileum in a concentration-dependent manner yet had no maximum relaxant effect even at a concentration of 10 microM. From Schild analysis the pA2 of pteleprenine on the guinea-pig ileum was found to be 6.6. The contraction of the ileum induced by 10 microM 1,1-dimethyl-4-phenylpiperazinium, a specific agonist of nicotinic acetylcholine receptors, was concentration-dependently suppressed by 10 nM-10 microM pteleprenine. In contrast, 0.1-10 microM pteleprenine did not antagonize the acetylcholine- and nicotine-induced negative inotropic contractile responses of the canine left atrium. These results show that pteleprenine has inhibitory action against nicotinic acetylcholine receptors in the guinea-pig ileum but not in the canine left atrium. Our findings also suggest that pteleprenine might be a novel lead compound as a nicotinic receptor antagonist.

A New Quinoline Epoxide from the Australian PlantDrummondita calida

A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the purification of a new quinoline alkaloid, (2' R)-2',3'-epoxy- N-methylatanine (1), along with eight known natural products, skimmianin, γ-fagarine, maculosidine, evolitrine, dictamnine, pteleine, N-methylatanine, and werneria chromene. Compound 1 displayed 74 % inhibition at 80 µM against a chloroquine -resistant Plasmodium falciparum strain (Dd2).

Docking and QSAR Studies of Camptothecin Derivatives as Inhibitor of DNA Topoisomerase-I

AbstractCamptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme Topoisomerase-I (Topo-I) and has shown remarkable anticancer activity in preliminary clinical trials. The major limitation is its low solubility and high adverse reaction. In the studied work, we performed molecular docking of CPT derivatives against Topo-I and developed the quantitative structure activity relationship (QSAR) model for anticancer activity screening. For QSAR, we used CPT and other anticancer drugs with its IC50 values. We used a total of forty seven anticancer drugs as training set and eight compounds as test set and thirty derivatives of CPT as query set. Total of fifty two chemical descriptors were used for the quantitative data calculation. Only four showed good correlation with the experimental activity. Forward feed regression method was used for development of multiple linear regression (MLR) QSAR model. Model showed acceptable regression coefficient (r2) 0.89 (i.e., 89% of correlation) and cross validation coefficient (rCV2) 0.86 (i.e., 86 % of prediction accuracy). After drug likeness test, ten compounds namely, MSB3a, MSB3b, MSB19, MSB22L, MSB22M, MSB22O, MSB22R, MSB25D, MSB37G and MSB39D, showed promising predicted anticancer activity and drug likeness properties. Out of ten, only six compounds namely, MSB19, MSB22L, MSBM, MSB22O, MSB22R and MSB37D indicate two times more activity than the parent CPT compound. In molecular docking studies, all the identified active CPT derivatives showed high binding affinity with Topo-I. QSAR study indicates that connectivity index, electron affinity, mol.wt. & ether group count highly contribute to inhibitory activity of CPT derivatives. These results can offer useful references for directing the molecular design of Topo-I inhibitor with improved anticancer activity.

Synthesis of Analogue to Camptothecine

Camptothecin (CPT) is a cytotoxic quinoline alkaloid, which inhibits the DNA enzyme topoisomerase I (topo I). It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata (Camptotheca, Happy tree), a tree native in China. CPT showed remarkable anticancer activity in preliminary clinical trials but also low solubility and (high) adverse drug reaction. Because of these disadvantages synthetic and medicinal chemists have developed numerous syntheses of Camptothecine [1][2][3] and various derivatives to increase the benefits of the chemical, with good results. In our method CPT analogues has be six steps starting from available material DL Malic acid. Keywords—Camptothecine, synthesis, analogue.

Quinoline alkaloids and friedelane-type triterpenes isolated from leaves and wood of Esenbeckia alata kunt (Rutaceae)

This work describes the phytochemical exploration of the ethanol extract from leaves and wood of Esenbeckia alata, leading to the isolation and identification of quinoline alkaloids 4-methoxy-3-(3'-methyl-but-2'-enyl)-N-methyl-quinolin-2(1 H)-one, N-methylflindersine, dictamine, kokusaginine, Γ-fagarine, flindersiamine, as well as the fridelane-type triterpenes, frideline, fridelanol and its acetate derivative. Identification of these compounds was based on full analyses of spectroscopic data (¹H, 13C, 1D, 2D, IR, MS) and comparison with data reported in literature. Compound 4-methoxy-3-(3'-methyl-but-2'-enyl)-N-methyl-quinolin-2(1 H)-one is reported for the first time for the genus Esenbeckia.

Seco-Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity

A novel seco-limonoid, rel-(1S,5R,9S,7R,8S,9R,10S,11R,13S,14R,15R,17R)-11,19-dihydroxy-7-acetoxy-7-deoxoichangin (raputiolide) (1), and two novel quinolone alkaloids N-methyl-2-phenoxyquinolin-4(1H)-one (heptaphyllone A) (2) and 6-methylbenzofuro[2,3-b]quinolin-4(1H)-one (heptaphyllone B) (3), along with the known seco-limonoid ichangin (4), were isolated from Raputia heptaphylla PITTIER (Rutaceae) stem bark. Five known alkaloids, N-methyl-8-methoxyflindersine (5), skimmianine (6), kokusaginine (7), dictamnine (8) and flindersiamine (9), were also isolated from R. heptaphylla leaves. Their structures were established on the basis of full spectroscopic data interpretation supported by data from the pertinent literature. seco-Limonoid 1 configuration was determined by enhanced nuclear Overhauser effect spectroscopy (NOESY) experiments and density functional theory (DFT) molecular modeling. The antileishmanial effect of the isolated compounds was evaluated on Leishmania Viannia panamensis (promastigotes and amastigotes). Whereas alkaloids 2-3, 6-8 and limonoid 4 exhibited no significant parasitocide activity against internalized L. (V.) panamensis amastigotes, limonoid 1 and alkaloid 5 had leishmanicidal activity on intracellular amastigotes (EC₅₀: 8.7 µg/ml) and promastigotes (EC(50): 14.3 µg/ml), respectively.

Completing the puzzle of aurachin biosynthesis in Stigmatella aurantiaca Sg a15

The aurachins are a family of secondary metabolites, with the main members aurachin A, B, C, and D, produced by the myxobacterium Stigmatella aurantiaca Sg a15. These isoprenoid quinoline alkaloids are classified as A-type or C-type aurachins according to the position of the farnesyl residue either at C4 or C3 of the quinoline core, respectively. Previous feeding studies revealed that the C-type aurachins are converted to A-type aurachins by late stage tailoring reactions. While the core gene cluster coding for the functionalities required for the biosynthesis of the basic structure aurachin D is known, neither of the genes encoding for the successively acting tailoring enzymes was known up to date, which was assumed to be due to a split cluster organisation. Here we describe the identification of a total of five genes, located upstream of the aurachin core cluster and at additional two loci elsewhere in the genome, encoding for the aforementioned functionalities. The generation and evaluation of respective inactivation mutants of S. aurantiaca Sg a15 allowed for the first time to propose an exhaustive model for aurachin biosynthesis. One of the deduced biosynthetic transformations corresponds to a pinacol rearrangement, an unprecedented tailoring reaction in secondary metabolite biosynthesis.