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. 2013 Feb 22;76(2):243-9.
doi: 10.1021/np3007414. Epub 2013 Jan 17.

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

Patrick C Still et al. J Nat Prod. .

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 α3β4 or α4β2 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 hα3β4 and hα4β2 receptor subtypes.

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Figures

Figure 1
Figure 1
Chemical shift difference values δ(S-R), for protons on the esterified piperidinol ring of 1, as established by the Mosher ester method.
Figure 2
Figure 2
Key COSY, HMBC and NOESY correlations of 1.
Figure 3
Figure 3. Key NOESY correlations and energy-minimized 3D structure of 2.
Figure 4
Figure 4. Effects of compounds 1–6 on recombinant nAChRs
An inhibition assay for each compound was performed using HEK tsA201 cells stably expressing hα3β4 and hα4β2 nAChRs. Cells were loaded with Calcium 5 NW dye and stimulated with 1 μM epibatidine in the presence of a single concentration of each test compound (10 μM), as described in the Experimental Section. Results are expressed as the percentage of the control, epibatidine-stimulated peak fluorescence level. Values represent the means ± SD of three to five experiments performed in triplicate. Percentage inhibitions achieved by compounds are shown in Table 2.

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