Lycoctonine

Quenching of quorum sensing in multi-drug resistant Pseudomonas aeruginosa: insights on halo-bacterial metabolites and gamma irradiation as channels inhibitors.[Pubmed:38600513]

Ann Clin Microbiol Antimicrob. 2024 Apr 10;23(1):31.

BACKGROUND: Anti-virulence therapy is a promising strategy to treat multi-drug resistant (MDR) pathogens. Pseudomonas aeruginosa is a potent opportunistic pathogen because of an array of virulence factors that are regulated by quorum sensing systems. METHODS: The virulence features of four multi-drug resistant P. aeruginosa strains were investigated upon exposure to the sub-lethal dose of gamma rays (1 kGy), and sub-inhibitory concentrations of bioactive metabolites recovered from local halophilic strains in comparison to control. Then, the gene expression of AHL-mediated quorum sensing systems (las/rhl) was quantitatively determined in treated and untreated groups by real-time PCR. RESULTS: The bioactive metabolites recovered from halophilic strains previously isolated from saline ecosystems were identified as Halomonas cupida (Halo-Rt1), H. elongate (Halo-Rt2), Vigibacillus natechei (Halo-Rt3), Sediminibacillus terrae (Halo-Rt4) and H. almeriensis (Halo-Rt5). Results revealed that both gamma irradiation and bioactive metabolites significantly reduced the virulence factors of the tested MDR strains. The bioactive metabolites showed a maximum efficiency for inhibiting biofilm formation and rhamnolipids production whereas the gamma irradiation succeeded in decreasing other virulence factors to lower levels in comparison to control. Quantitative-PCR results showed that AHL-mediated quorum sensing systems (las/rhl) in P. aeruginosa strains were downregulated either by halo-bacterial metabolites or gamma irradiation in all treatments except the upregulation of both lasI internal gene and rhlR intact gene in P. aeruginosa NCR-RT3 and both rhlI internal gene and rhlR intact gene in P. aeruginosa U3 by nearly two folds or more upon exposure to gamma irradiation. The most potent result was observed in the expression of lasI internal gene that was downregulated by more than ninety folds in P. aeruginosa NCR-RT2 after treatment with metabolites of S. terrae (Halo-Rt4). Analyzing metabolites recovered from H. cupida (Halo-Rt1) and H. elongate (Halo-Rt2) using LC-ESI-MS/MS revealed many chemical compounds that have quorum quenching properties including glabrol, 5,8-dimethoxyquinoline-2-carbaldehyde, linoleoyl ethanolamide, agelasine, penigequinolones derivatives, berberine, tetracosanoic acid, and liquidambaric lactone in the former halophile and phloretin, Lycoctonine, fucoxanthin, and crassicauline A in the latter one. CONCLUSION: QS inhibitors can significantly reduce the pathogenicity of MDR P. aeruginosa strains; and thus can be an effective and successful strategy for treating antibiotic resistant traits.

Synthesis and biological evaluation of lycoctonine derivatives with cardiotonic and calcium channels inhibitory activities.[Pubmed:38503027]

Bioorg Chem. 2024 May;146:107297.

In our previous study, a screening of a variety of lycotonine-type diterpenoid alkaloids were screened for cardiotonic activity revealed that Lycoctonine had moderate cardiac effect. In this study, a series of structurally diverse of Lycoctonine were synthesized by modifying on B-ring, D-ring, E-ring, F-ring, N-atom or salt formation on Lycoctonine skeleton. We evaluated the cardiotonic activity of the derivatives by isolated frog heart, aiming to identify some compounds with significantly enhanced cardiac effects, among which compound 27 with a N-isobutyl group emerged as the most promising cardiotonic candidate. Furthermore, the cardiotonic mechanism of compound 27 was preliminarily investigated. The result suggested that the cardiotonic effect of compound 27 is related to calcium channels. Patch clamp technique confirmed that the compound 27 had inhibitory effects on Ca(V)1.2 and Ca(V)3.2, with inhibition rates of 78.52 % +/- 2.26 % and 79.05 % +/- 1.59 % at the concentration of 50 muM, respectively. Subsequently, the protective effect of 27 on H9c2 cells injury induced by cobalt chloride was tested. In addition, compound 27 can alleviate CoCl(2)-induced myocardial injury by alleviating calcium overload. These findings suggest that compound 27 was a new structural derived from Lycoctonine, which may serve as a new lead compound for the treatment of heart failure.

Diterpenoid Alkaloids from Delphinium liangshanense.[Pubmed:38191840]

Chem Biodivers. 2024 Jan 8:e202301923.

Two new C19-diterpenoid alkaloids of the Lycoctonine-type (liangshanine A and liangshanine B) and nineteen known compounds (3-21) were isolated from the whole plant of Delphinium liangshanense W. T. Wang, and all the compounds were identified by different spectroscopic analyses, such as IR, HR-ESI-MS and NMR. All the compounds were isolated from this plant for the first time and tested for the anti-proliferation effects on MH7A and SF9 cells to figure their anti-rheumatoid arthritis and anti-insect activity, but none of them showed remarkable activity.

Diterpenoid alkaloids from two species of Delphinium.[Pubmed:36331432]

J Asian Nat Prod Res. 2023 Jul-Aug;25(8):718-730.

Four new compounds (1-4) were isolated from the whole plants of two species of Delphinium, including two C(20)-diterpenoid alkaloids, umbrodines A and B (1 and 2), and a dibenzoxazepinone, umbrolide A (3) from Delphinium umbrosum Hand.-Mazz. and a C(20)-diterpenoid alkaloid, kingiadine (4) from Delphinium kingianum Bruhl. ex Huth. Ten known diterpenoid alkaloids were also isolated. Their structures were elucidated via HR-ESIMS, IR, and NMR data. Lycoctonine (11) and delectinine (12) exhibited appreciable cardiac activity. Furthermore, 11 and 12 showed cardioprotective effects against doxorubicin-induced toxicity in H9c2 cells, with the maximum protection rates of 61.63% and 51.18%, respectively.

Bioactivity inspired C(19)-diterpenoid alkaloids for overcoming multidrug-resistant cancer.[Pubmed:35614289]

J Nat Med. 2022 Sep;76(4):796-802.

The pharmacological activities of C(19)-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or Lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of Lycoctonine-type C(19)-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1-14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 muM verapamil, and derivatives 4 and 13 were more effective than 5 muM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.

Diterpenoid Alkaloids Isolated from Delphinium brunonianum and Their Inhibitory Effects on Hepatocytes Lipid Accumulation.[Pubmed:35408656]

Molecules. 2022 Mar 30;27(7):2257.

This research aimed to excavate compounds with activity reducing hepatocytes lipid accumulation from Delphinium brunonianum. Four novel diterpenoid alkaloids, brunodelphinine B-E, were isolated from D. brunonianum together with eleven known diterpenoid alkaloids through a phytochemical investigation. Their structures were elucidated by comprehensive spectroscopy methods including HR-ESI-MS, NMR, IR, UV, CD, and single-crystal X-ray diffraction analysis. The inhibitory effects of a total of 15 diterpenoid alkaloids on hepatocytes lipid accumulation were evaluated using 0.5 mM FFA (oleate/palmitate 2:1 ratio) to induce buffalo rat liver (BRL) cells by measuring the levels of triglyceride (TG), total cholesterol (TC), alanine transaminase (ALT), aspartate transaminase (AST), and the staining of oil red O. The results show that five diterpenoid alkaloids-brunodelphinine E (4), delbruline (5), Lycoctonine (7), delbrunine (8), and sharwuphinine A (12)-exhibited significant inhibitory effects on lipid accumulation in a dose-dependent manner and without cytotoxicity. Among them, sharwuphinine A (12) displayed the strongest inhibition of hepatocytes lipid accumulation in vitro. Our research increased the understanding on the chemical composition of D. brunonianum and provided experimental and theoretical evidence for the active ingredients screened from this herbal medicine in the treatment of the diseases related to lipid accumulation, such as non-alcoholic fatty liver disease and hyperlipidemia.

A new diterpenoid alkaloid from Delphinium gyalanum C. Marquand & Airy Shaw.[Pubmed:34241556]

Nat Prod Res. 2023 Jan;37(1):130-135.

A new C(19)-diterpenoid alkaloid named gyalanutine A (1) and fourteen known compounds 2-15 were isolated from the plant of Delphinium gyalanum C. Marquand & Airy Shaw. Compound 1 displayed an unusual Lycoctonine-type C(19)-diterpenoid alkaloid skeleton with the cleavage of N-C(19) and C(7)-C(17) bonds, and the construction of the N-C(7) bond. Structures were identified by multiple spectroscopic analyses including 1 D, 2 D NMR, IR and HR-ESI-MS. Compounds were tested for acetylcholinesterase inhibitory and anti-inflammatory activity.

The chemistry and pharmacology of alkaloids and allied nitrogen compounds from Artemisia species: A review.[Pubmed:31453659]

Phytother Res. 2019 Oct;33(10):2661-2684.

Several reviews have been published on Artemisia's derived natural products, but it is the first attempt to review the chemistry and pharmacology of more than 80 alkaloids and allied nitrogen compounds obtained from various Artemisia species (covering the literature up to June 2018). The pharmacological potential and unique skeleton types of certain Artemisia's alkaloids provoke the importance of analyzing Artemisia species for bioactive alkaloids and allied nitrogen compounds. Among the various types of bioactive Artemisia's alkaloids, the main classes were the derivatives of rupestine (pyridine-sesquiterpene), Lycoctonine (diterpene), pyrrolizidine, purines, polyamine, peptides, indole, piperidine, pyrrolidine, alkamides, and flavoalkaloids. The rupestine derivatives are Artemisia's characteristic alkaloids, whereas the rest are common alkaloids found in the family Asteraceae and chemotaxonomically links the genus Artemisia with the tribes Anthemideae. The most important biological activities of Artemisia's alkaloids are including hepatoprotective, local anesthetic, beta-galactosidase, and antiparasitic activities; treatment of angina pectoris, opening blocked arteries, as a sleep-inducing agents and inhibition of HIV viral protease, CYP450, melanin biosynthesis, human carbonic anhydrase, [3H]-AEA metabolism, kinases, and DNA polymerase beta(1) . Some of the important nitrogen metabolites of Artemisia include pellitorine, zeatin, tryptophan, rupestine, and aconitine analogs, which need to be optimized and commercialized further.

Norditerpenoid alkaloids from Delphinium pseudoaemulans C. Y. Yang et B. Wang.[Pubmed:30340117]

Phytochemistry. 2018 Dec;156:234-240.

Eight previously undescribed norditerpenoid alkaloids, pseudophnines A-D, pseudorenines A-B, and pseudonidines A-B, together with ten known norditerpenoid alkaloids, tianshanisine E, sharwuphinine B, potanisine A, Lycoctonine, delbruline, isondelpheline, delavaines A-B, and shawurenines A-B were isolated from the whole plant of Delphinium pseudoaemulans C. Y. Yang et B. Wang. Their structures were established on the basis of spectroscopic analyses, including HR-ESI-MS, 1D and 2D NMR analysis. Additionally, no cytotoxicity was observed against A549 and HeLa cancer cells of these diterpenoid alkaloids when evaluated in vitro using the MTT method.

Diterpenoid alkaloids from Delphinium naviculare var. lasiocarpum with their antifeedant activity on Spodoptera exigua.[Pubmed:29781312]

Nat Prod Res. 2019 Nov;33(22):3254-3259.

A new Lycoctonine diterpenoid alkaloid navicularine, along with eighteen known diterpenoid alkaloids, were isolated from the whole plant of Delphinium naviculare var. lasiocarpum. Their structures were elucidated on the base of extensive spectroscopic analysis (HR-ESI-MS and NMR) and comparison with data reported in the literature. Most of alkaloids were tested for their antifeedant activity against larvae of Spodoptera exigua (Hubner). The compound shawurensine showed considerably potent antifeedant activity (EC(50) = 0.42 and 0.81 mg/cm(2) in the choice test and no choice test, respectively).

Diterpenoid Alkaloids from Consolida regalis S. F.Gray subsp.paniculata (Host) Soo var. paniculata.[Pubmed:28813032]

Sci Pharm. 2017 Aug 16;69(1):61-65.

Seven diterpenoid alkaloids : delcosine(1), delsoline(2), gigactonine(3), Lycoctonine(4), takaosamine(5), atisine(6) and hetisinone(7) have been isolated from the aerial parts of Consolida regalis subsp. paniculata var. paniculata. The presence of compounds 1,2,5,6 and 7 in this plant has not been previously reported.

Selective dual cholinesterase inhibitors from Aconitum laeve.[Pubmed:28463565]

J Asian Nat Prod Res. 2018 Feb;20(2):172-181.

New Lycoctonine-type dual cholinesterase inhibitor, swatinine-C (1), along with three known norditerpenoid alkaloids, hohenackerine (2), aconorine (5) and lappaconitine (6) and two synthetically known but phytochemically new benzene derivatives, methyl 2-acetamidobenzoate (3) and methyl 4-[2-(methoxycarbonyl)anilino]-4-oxobutanoate (4), was isolated from the roots of A. laeve. Structures of new and known compounds (1-6) were established on the basis of latest spectroscopic techniques and by close comparison with the data available in literature. In vitro, compounds (1-6) were tested against AChE and BChE inhibitory activities. Compounds 1 and 2 showed competitive inhibition against AChE (IC(50 )= 3.7 muM, 4.53 muM) and BChE (IC(50 )= 12.23 muM, 9.94 muM), respectively. Compounds 5 and 6 showed promising noncompetitive type of inhibitory profile against AChE (IC(50 )= 2.51 and 6.13 muM) only. Compounds 3 and 4 showed weak inhibitory profile against both AChE and BChE.

A new diterpenoid alkaloid isolated from Delphinium caeruleum.[Pubmed:28259252]

Chin J Nat Med. 2017 Jan;15(1):45-48.

The present study was designed to determine the chemical constituents of Delphinium caeruleum Jacq. ex Camb.. The chemical constituents were isolated and purified by column chromatography with silica gel, ODS, and Sephadex LH-20. Their structures were elucidated by IR, MS, and NMR. Ten compounds were obtained and identified as caerudelphinine A (1), Lycoctonine (2), talitine B (3), talitine A (4), talitine C (5), tatsienine-V (6), d-magnoflorine (7), 2-trimethyl-ammonio-3-(3-indolyl) propionate (8), vakhmatine (9), and delatisine (10). Compound 1 was a new Lycoctonine-type C19-diterpenoid alkaloid, and compounds 4-10 were isolated from this plant for the first time.

Further Studies on Structure-Cardiac Activity Relationships of Diterpenoid Alkaloids.[Pubmed:26882669]

Nat Prod Commun. 2015 Dec;10(12):2075-84.

The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1alpha-OMe or 1alpha-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, Lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3alpha-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6alpha-OMe, 13-OH, 15alpha-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.

Norditerpenoid alkaloids from Delphinium anthriscifolium.[Pubmed:26245883]

J Asian Nat Prod Res. 2016;18(2):141-6.

Two new norditerpenoid alkaloids with Lycoctonine skeleton, anthriscifolcones A (1) and B (2), were isolated from the whole plant of Delphinium anthriscifolium var. Majus by extensive column chromatography. Their structures were established by IR, MS, (1)H NMR, (13)C NMR, and 2D NMR methods (including HSQC, (1)H-(1)H COSY, HMBC, and NOESY experiments).