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Macroline, talpinine, and sarpagine alkaloids from Alstonia penangiana. An NMR-based method for differentiating between A. penangiana and A. macrophylla

Yeap JS, Tan CH, Yong KT, Lim KH, Lim SH, Low YY, et al.

Phytochemistry, 2020 Aug;176:112391.

PMID: 32387883 DOI: 10.1016/j.phytochem.2020.112391

Fourteen previously undescribed alkaloids comprising two N-1-hydroxymethylmacroline alkaloids, one talpinine-type oxindole acetal, a pair of equilibrating talpinine-type oxindole hemiacetals, eight oxidized derivatives of sarpagine- and akuammiline-type indole alkaloids, in addition to alstochalotine a diastereomer of gelsochalotine recently isolated from Gelsemium elegans, were isolated from the leaf and stem-bark extracts of Alstonia penangiana. The structures and relative configurations of these alkaloids were established using NMR, MS, and in one instance, confirmed by X-ray diffraction analysis. An NMR-based method is described as a useful chemotaxonomic tool for differentiating between A. penangiana and A. macrophylla. Several of the alkaloids isolated showed appreciable growth inhibitory effects when tested against a number of human cancer cell lines.

Matched MeSH terms: Indole Alkaloids

Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata

Kam TS, Pang HS, Choo YM, Komiyama K

Chem Biodivers, 2004 Apr;1(4):646-56.

PMID: 17191876

Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/toxicity; Indole Alkaloids/chemistry

Biosynthetic Enantiodivergence in the Eburnane Alkaloids from Kopsia

Chong KW, Yeap JS, Lim SH, Weber JF, Low YY, Kam TS

J Nat Prod, 2017 11 22;80(11):3014-3024.

PMID: 29087707 DOI: 10.1021/acs.jnatprod.7b00621

Reexamination of the absolute configuration of recently isolated eburnane alkaloids from Malaysian Kopsia and Leuconotis species by X-ray diffraction analysis and ECD/TDDFT has revealed the existence of biosynthetic enantiodivergence. Three different scenarios are discerned with respect to the composition of the enantiomeric eburnane alkaloids in these plants: first, where the new eburnane congeners possess the same C-20, C-21 absolute configurations as the common eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, eburnamenine) occurring in the same plant; second, where the new eburnane congeners possess opposite or enantiomeric C-20, C-21 absolute configurations compared to the common eburnane alkaloids found in the same plant; and, third, where the four common eburnane alkaloids were isolated as racemic or scalemic mixtures, while the new eburnane congeners were isolated as pure enantiomers with a common C-20, C-21 configuration (20α, 21α). Additionally, the same Kopsia species (K. pauciflora) found in two different geographical locations (Peninsular Malaysia and Malaysian Borneo) showed different patterns in the composition of the enantiomeric eburnane alkaloids. Revision of the absolute configurations of a number of new eburnane congeners (previously assigned based on the assumption of a common biogenetic origin to that of the known eburnane alkaloids co-occurring in the same plant) is required based on the present results.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/metabolism; Indole Alkaloids/chemistry

Lumusidines A-D and villalstonidine F, macroline-macroline and macroline-pleiocarpamine bisindole alkaloids from Alstonia macrophylla

Lim SH, Low YY, Subramaniam G, Abdullah Z, Thomas NF, Kam TS

Phytochemistry, 2013 Mar;87:148-56.

PMID: 23200029 DOI: 10.1016/j.phytochem.2012.11.005

Lumusidines A-D, bisindole alkaloids of the macroline-macroline type, and one of the macroline-pleiocarpamine type, villalstonidine F, were isolated from the stem-bark extract of Alstonia macrophylla (Apocynaceae). The structures and absolute configurations of these alkaloids were established using NMR, MS, and X-ray diffraction analyses.

Matched MeSH terms: Indole Alkaloids/chemistry*

Biologically active indole and bisindole alkaloids from Tabernaemontana divaricata

Kam TS, Pang HS, Lim TM

Org Biomol Chem, 2003 Apr 21;1(8):1292-7.

PMID: 12929658

The ethanol extract of the leaves of Tabernaemontana divaricata (double flower variety) provided a total of 23 alkaloids, including the new aspidosperma alkaloids, taberhanine, voafinine, N-methylvoafinine, voafinidine, voalenine and the new bisindole alkaloid, conophyllinine in addition to the previously known, biologically active bisindole, conophylline and its congener, conofoline. The structures of the new alkaloids were established by spectroscopic methods. The preparation and characterization of the corresponding quinones of the biologically active bisindoles are also described in relation to a structure-activity study of these compounds with respect to their action in stimulating insulin expression.

Matched MeSH terms: Indole Alkaloids/chemistry*

Absolute Configuration of Alkaloids from Uncaria longiflora through Experimental and Computational Approaches

Salim F, Yunus YM, Anouar EH, Awang K, Langat M, Cordell GA, et al.

J Nat Prod, 2019 11 22;82(11):2933-2940.

PMID: 31686505 DOI: 10.1021/acs.jnatprod.8b00380

The structure elucidation of three new alkaloids named isoformosaninol (1), formosaninol (2), and longiflorine (3), isolated from the leaves of Uncaria longiflora var. pteropoda (Miq.) Ridsdale, along with their biosynthetic pathways are discussed. Their absolute structures were determined through a combination of physical data interpretation and quantum chemical calculations using the time-dependent density functional theory (TDDFT) method.

Matched MeSH terms: Indole Alkaloids/analysis

Fulltext Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. Leaves

Veeramohan R, Zamani AI, Azizan KA, Goh HH, Aizat WM, Razak MFA, et al.

PLoS One, 2023;18(3):e0283147.

PMID: 36943850 DOI: 10.1371/journal.pone.0283147

The fresh leaves of Mitragyna speciosa (Korth.) Havil. have been traditionally consumed for centuries in Southeast Asia for its healing properties. Although the alkaloids of M. speciosa have been studied since the 1920s, comparative and systematic studies of metabolite composition based on different leaf maturity levels are still lacking. This study assessed the secondary metabolite composition in two different leaf stages (young and mature) of M. speciosa, using an untargeted liquid chromatography-electrospray ionisation-time-of-flight-mass spectrometry (LC-ESI-TOF-MS) metabolite profiling. The results revealed 86 putatively annotated metabolite features (RT:m/z value) comprising 63 alkaloids, 10 flavonoids, 6 terpenoids, 3 phenylpropanoids, and 1 of each carboxylic acid, glucoside, phenol, and phenolic aldehyde. The alkaloid features were further categorised into 14 subclasses, i.e., the most abundant class of secondary metabolites identified. As per previous reports, indole alkaloids are the most abundant alkaloid subclass in M. speciosa. The result of multivariate analysis (MVA) using principal component analysis (PCA) showed a clear separation of 92.8% between the young and mature leaf samples, indicating a high variance in metabolite levels between them. Akuammidine, alstonine, tryptamine, and yohimbine were tentatively identified among the many new alkaloids reported in this study, depicting the diverse biological activities of M. speciosa. Besides delving into the knowledge of metabolite distribution in different leaf stages, these findings have extended the current alkaloid repository of M. speciosa for a better understanding of its pharmaceutical potential.

Matched MeSH terms: Indole Alkaloids/analysis

Fulltext Naucline, a new indole alkaloid from the bark of Nauclea officinalis

Liew SY, Mukhtar MR, Hadi AH, Awang K, Mustafa MR, Zaima K, et al.

Molecules, 2012 Apr 02;17(4):4028-36.

PMID: 22469596 DOI: 10.3390/molecules17044028

A new indole alkaloid, naucline (1) together with four known alkaloids, angustine (2), angustidine (3), nauclefine (4) and naucletine (5), were isolated from the bark of Nauclea officinalis. The structures of all isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS-IT-TOF. In addition to that of alkaloid 1, the complete 13C-NMR data of naucletine (5) were also reported. Naucline (1) showed a moderate vasorelaxant activity (90% relaxation at 1 × 10(-5) M) whereas, angustine (2), nauclefine (4), and naucletine (5) showed potent vasorelaxant activity (more than 90% relaxation at 1 × 10(-5) M) on an isolated rat aorta.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry*

Grandilodines A-C, biologically active indole alkaloids from Kopsia grandifolia

Yap WS, Gan CY, Low YY, Choo YM, Etoh T, Hayashi M, et al.

J Nat Prod, 2011 May 27;74(5):1309-12.

PMID: 21428274 DOI: 10.1021/np200008g

Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry

Aspidospermatan-aspidospermatan and eburnane-sarpagine bisindole alkaloids from Leuconotis

Gan CY, Low YY, Robinson WT, Komiyama K, Kam TS

Phytochemistry, 2010 Aug;71(11-12):1365-70.

PMID: 20542302 DOI: 10.1016/j.phytochem.2010.05.015

Leucofoline and leuconoline, representing the first members of the aspidospermatan-aspidospermatan and eburnane-sarpagine subclasses of the bisindole alkaloids, respectively, were isolated from the Malayan Leuconotis griffithii. The structures of these bisindole alkaloids were established using NMR and MS analysis, and in the case of leuconoline, confirmed by X-ray diffraction analysis. Both alkaloids showed weak cytotoxicity towards human KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry

Strychnan and secoangustilobine A type alkaloids from Alstonia spatulata. Revision of the C-20 configuration of scholaricine

Tan SJ, Low YY, Choo YM, Abdullah Z, Etoh T, Hayashi M, et al.

J Nat Prod, 2010 Nov 29;73(11):1891-7.

PMID: 21043460 DOI: 10.1021/np100552b

A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry

Leucoridines A-D, cytotoxic Strychnos-Strychnos bisindole alkaloids from Leuconotis

Gan CY, Etoh T, Hayashi M, Komiyama K, Kam TS

J Nat Prod, 2010 Jun 25;73(6):1107-11.

PMID: 20515042 DOI: 10.1021/np1001187

Four new bisindole alkaloids of the Strychnos-Strychnos type, leucoridines A-D (1-4), were isolated from the stem-bark extract of Leuconotis griffithii. Alkaloids 1-4 showed moderate cytotoxicity against drug-sensitive and vincristine-resistant human KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry

Bisnicalaterine A, a vobasine-vobasine bisindole alkaloid from Hunteria zeylanica

Nugroho AE, Hirasawa Y, Kawahara N, Goda Y, Awang K, Hadi AH, et al.

J Nat Prod, 2009 Aug;72(8):1502-6.

PMID: 19388660 DOI: 10.1021/np900115q

A new bisindole alkaloid, bisnicalaterine A (1), consisting of two vobasine-type skeletons, and 3-epivobasinol (2) and 3-O-methylepivobasinol (3), with vobasine-type skeletons, were isolated from the leaves of Hunteria zeylanica, and their structures were elucidated on the basis of spectroscopic data and chemical correlation. Bisnicalaterine A showed moderate cytotoxicity against various human cancer cell lines.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry

Leuconoxine, kopsinitarine, kopsijasmine, and kopsinone derivatives from Kopsia

Lim SH, Sim KM, Abdullah Z, Hiraku O, Hayashi M, Komiyama K, et al.

J Nat Prod, 2007 Aug;70(8):1380-3.

PMID: 17608533

Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry

Biologically active indole alkaloids from Kopsia arborea

Lim KH, Hiraku O, Komiyama K, Koyano T, Hayashi M, Kam TS

J Nat Prod, 2007 Aug;70(8):1302-7.

PMID: 17665953

Nine new indole alkaloids, rhazinoline (1), 19(S)-methoxytubotaiwine (2), 19(R)-methoxytubotaiwine (3), kopsamidine A (4), kopsamidine B (5), kopsinidine A (6), kopsinidine B (7), paucidactine C (8), and pericine N-oxide (9), in addition to several recently reported novel indoles and 34 other known ones, were obtained from the stem-bark extract of the Malayan Kopsia arborea. The structures were determined using NMR and MS analysis. Valparicine (12) showed pronounced cytotoxic effects against KB and Jurkat cells (IC(50) 13.0 and 0.91 microM, respectively).

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry

Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa

Takayama H

Chem Pharm Bull (Tokyo), 2004 Aug;52(8):916-28.

PMID: 15304982

The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the mitragynine derivatives, 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry*

Reflexin A, a new indole alkaloid from Rauvolfia reflexa induces apoptosis against colon cancer cells

Fadaeinasab M, Karimian H, Omar H, Taha H, Khorasani A, Banisalam B, et al.

J Asian Nat Prod Res, 2020 May;22(5):474-488.

PMID: 30945944 DOI: 10.1080/10286020.2019.1588888

One new indole alkaloid, reflexin A (1), and two known indoles, macusine B (2) and vinorine (3), were isolated from the bark of Rauvolfia reflexa. Their structures were elucidated by 1D and 2D NMR, UV, IR, and MS spectroscopic analyses. Compound 1 displayed anticancer activity against HCT-116 colon cancer cells with an IC50 value of 30.24 ± 0.75 µM. The results implied that the newly isolated 1 induced apoptosis in HCT-116 cells, suggesting its possible role as an anticancer agent. In vivo acute toxicity study was performed on compound 1 to evaluate its safety profile.

Matched MeSH terms: Indole Alkaloids

Combinations of indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of nasopharyngeal carcinoma cell lines

Domnic G, Jeng-Yeou Chear N, Abdul Rahman SF, Ramanathan S, Lo KW, Singh D, et al.

J Ethnopharmacol, 2021 Oct 28;279:114391.

PMID: 34224811 DOI: 10.1016/j.jep.2021.114391

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaf of M. speciosa is used as a remedy in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents.

AIM OF THE STUDY: To assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines.

MATERIALS AND METHODS: The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line NPC/HK1, and therefore, was chosen for further fractionation and purification. NPC cell lines NPC/HK1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids combinations in 2D monolayer culture. The effect of cisplatin and mitragynine as a combination on cell migration was tested using in vitro wound healing and spheroid invasion assays.

RESULTS: In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the NPC/HK1 cell line. Both NPC cell lines (NPC/HK1 and C666-1) were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitized the NPC/HK1 and C666-1 cells to cisplatin at ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, the combination also of mitragynine and cisplatin inhibited growth and invasion of NPC/HK1 spheroids in a dose-dependent manner. In addition, the spheroids did not rapidly develop resistance to the drug combinations at higher concentrations over 10 days.

CONCLUSION: Our data indicate that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further elucidation focusing on the drug mechanistic studies and in vivo studies are necessary to support delineate the therapeutic applicability of M. speciosa alkaloids for NPC treatment.

Matched MeSH terms: Indole Alkaloids/administration & dosage; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry*

Criofolinine and vernavosine, new pentacyclic indole alkaloids incorporating pyrroloazepine and pyridopyrimidine moieties derived from a common yohimbine precursor

Nge CE, Gan CY, Lim KH, Ting KN, Low YY, Kam TS

Org. Lett., 2014 Dec 19;16(24):6330-3.

PMID: 25454201 DOI: 10.1021/ol503072g

Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/chemistry*

Oxidized derivatives of macroline, sarpagine, and pleiocarpamine alkaloids from Alstonia angustifolia

Tan SJ, Lim JL, Low YY, Sim KS, Lim SH, Kam TS

J Nat Prod, 2014 Sep 26;77(9):2068-80.

PMID: 25211145 DOI: 10.1021/np500439u

A total of 20 new indole alkaloids comprising mainly oxidized derivatives of macroline- (including alstofonidine, a macroline indole incorporating a butyrolactone ring-F), pleiocarpamine-, and sarpagine-type alkaloids were isolated from the bark and leaf extracts of Alstonia angustifolia. The structures and relative configurations of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 3, 7, 35, and 41 showed moderate to weak activity, while 21 showed strong activity in reversing multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/chemistry

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