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Alkaloids from Microcos paniculata with cytotoxic and nicotinic receptor antagonistic activities.

ABSTRACT: Microcos paniculata is a large shrub or small tree that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A-C (1-3), as well as three known compounds, inclusive of microcosamine A (4), 7'-(3',4'-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compounds 1-6 and 1a (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human ?3?4 or ?4?2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (1) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the h?3?4 and h?4?2 receptor subtypes.

SUBMITTER: Still PC

PROVIDER: S-EPMC3580017 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Alkaloids from Microcos paniculata with cytotoxic and nicotinic receptor antagonistic activities.

Still Patrick C PC Yi Bitna B González-Cestari Tatiana F TF Pan Li L Pavlovicz Ryan E RE Chai Hee-Byung HB Ninh Tran Ngoc TN Li Chenglong C Soejarto Djaja Djendoel DD McKay Dennis B DB Kinghorn A Douglas AD

Journal of natural products 20130117 2

Microcos paniculata is a large shrub or small tree that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A-C (1-3), as well as three known compounds, inclusive of microcosamine A (4), 7'-(3',4'-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compound ...[more]

PMID: 23327794

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Project description:As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R², Q², and P² for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R² = 0.99, Q² = 0.83 and P² = 0.79 for anti-Tbr activity and R² = 0.94, Q² = 0.64, P² = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure?activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.

Project description:Natural products obtained from species of the genus Abuta (Menispermaceae) are known as ethnobotanicals that are attracting increasing attention due to a wide range of their pharmacological properties. In this study, the alkaloids stepharine and 5-N-methylmaytenine were first isolated from branches of Abuta panurensis Eichler, an endemic species from the Amazonian rainforest. Structure of the compounds was elucidated by a combination of 1D and 2D NMR spectroscopic and MS and HRMS spectrometric techniques. Interaction of the above-mentioned alkaloids with acetylcholinesterase enzyme and interleukins IL-6 and IL-8 was investigated in silico by molecular docking. The molecules under investigation were able to bind effectively with the active sites of the AChE enzyme, IL-6, and IL-8 showing affinity towards the proteins. Along with the theoretical study, acetylcholinesterase enzyme inhibition, cytotoxic, and immunomodulatory activity of the compounds were assessed by in vitro assays. The data obtained in silico corroborate the results of AChE enzyme inhibition, the IC50 values of 61.24?M for stepharine and 19.55?M for 5-N-methylmaytenine were found. The compounds showed cytotoxic activity against two tumor cell lines (K562 and U937) with IC50 values ranging from 11.77 ?M to 28.48 ?M. The in vitro assays revealed that both alkaloids were non-toxic to Vero and human PBMC cells. As for the immunomodulatory activity, both compounds inhibited the production of IL-6 at similar levels. Stepharine inhibited considerably the production of IL-8 in comparison to 5-N-methylmaytenine, which showed a dose dependent action (inhibitory at the IC50 dose, and stimulatory at the twofold IC50 one). Such a behavior may possibly be explained by different binding modes of the alkaloids to the interleukin structural fragments. Occurrence of the polyamine alkaloid 5-N-methylmaytenine was reported for the first time for the Menispermaceae family, as well as the presence of stepharine in A. panurensis.

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Alkaloids from Microcos paniculata with cytotoxic and nicotinic receptor antagonistic activities.

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Alkaloids from Microcos paniculata with cytotoxic and nicotinic receptor antagonistic activities.

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