Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues

Twenty-five amide alkaloids (1–25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39–48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC₅₀ = 4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC₅₀ >40 μM) against MDA-MB-231 and SK-BR-3. Structure–activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype.     

Alkaloids and monoterpenes from the leaves of Isatis tinctoria Linnaeus and their chemotaxonomic significance

Phytochemical investigation of the leaves of Isatis tinctoria Linnaeus led to the isolation of thirty compounds, including thirteen indole alkaloids (1–13), seven quinazolinone alkaloids (14–20), two quinoline alkaloids (21–22), one quindoline alkaloid (23), one simple amide alkaloid (24) and six monoterpenes (25–30). According to spectroscopic data analysis and comparison with the previously reported literature, their structures were elucidated. Among them, six compounds (12, 13, 17, and 22–24) have not been reported from the family Brassicaceae and eight compounds (3, 7, and 25–30) were isolated from the genus Isatis for the first time. Furthermore, the chemotaxonomic significance of isolated compounds has also been elaborated.     

Chemical constituents of Gardneria ovata wall

A phytochemical investigation on the aerial parts of Gardneria ovata Wall resulted in the isolation and identification of 14 compounds, including three gardneria glycoalkaloids (1–2 and 6), seven gardneria alkaloids (3–5 and 7–10), and four oxindole alkaloids (11–14). The structure of compound 1 was elucidated by means of spectroscopic analysis, including HRESIMS together with 1D and 2D NMR experiments. Compounds 1–2 and 11–14 are the first time reported from of G. ovate, while the compounds 3–4, 6, and 8 are also the characteristic secondary metabolites of the title plant. The chemotaxonomic significance and distribution of these monoterpenoid indole alkaloids in Gardneria genus are discussed.     

Chemical constituents of Melodinus hemsleyanus diels

Phytochemical investigation on the aerial parts of Melodinus hemsleyanus diels (Jahrb, Syst, 1995) led to the isolation and identification of 27 compounds, including fifteen aspidosperma-type alkaloids (1–15), four quinoline-type alkaloids (16–19), three quebrachamine-type alkaloids (20–22), and five eburna-type alkaloids (23–27). The structure of compound 1 was elucidated by means of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR experiments. Compounds 1–2, 6, 10, 12, 13, 15, 16 and 20–27 are herein reported for the first time from the studied plant, while the compounds 1–2 and 21 have not previously been recorded in the genus Melodinus. The aspidosperma-type monoterpenoid indole alkaloids in M. hemsleyanus could serve as chemotaxonomic markers.     

Taxonomic significance and antitumor activity of alkaloids from Clausena lansium Lour. Skeels (Rutaceae)

Phytochemical analysis of isolates from the aerial parts of Clausena lansium Lour. Skeels (Rutaceae) led to the identification of 14 alkaloids, including two indole alkaloids (1 and 2), one quinoline alkaloid (3), two pyridine alkaloids (4 and 5), four carbazole alkaloids (6–9) and five amides alkaloids (10–14). The phytochemical structures of the alkaloids were established by means of NMR and MS spectral analyses. Compounds (4, 5, 14) were three new natural products, while 1–3 and 10 were firstly reported from the genus Clausena and 8 and 9 were isolated from this species for the first time. The chemotaxonomic significance of these isolated alkaloids has also been discussed. All the isolated alkaloids were tested for their cytotoxic activity against Hela cancer cell line. Among them, four carbazole alkaloids 6–9 exhibited weak cytotoxicity with IC₅₀ values ranging from 69.31 to 138.32 μM.     

Monoterpenoid indole alkaloids from Kopsia hainanensis Tsiang

A phytochemical investigation on the twigs and leaves of Kopsia hainanensis Tsiang resulted in the isolation and identification of 18 alkaloids, including two sarpagine type alkaloids (1 and 2), five eburnane type alkaloids (3–7), three aspidofractinine type alkaloids (8–10), one vincadine type alkaloid (11), three akuammiline type alkaloids (12–13 and 15), one corynanthean type alkaloid (14), two ajmalicine-like type alkaloids (16 and 17), and one aspidospermine type alkaloid (18). The new structure of compound 1 was elucidated by means of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR experiments. Compounds 1–2, 4–5, 7, and 10–17 are herein reported for the first time from this plant, while the compounds 1, 2, 7, and 12–17 have not been previously recorded in the Kopsia genus. The chemotaxonomic significance and distribution of these monoterpenoid indole alkaloids in Kopsia genus are discussed.     

Chemical constituents from Piper boehmeriifolium (Miq.) Wall. ex C. DC

The chemical investigation of whole plants Piper boehmeriifolium (Miq.) Wall. ex C. DC. led to the isolation of 22 compounds, including two lignans (1–2), sixteen amide alkaloids (3–18), one diterpene (19), two monoterpenes (20–21), and one phenylpropanoid (22). Their structures were elucidated by extensive spectroscopic analyses including NMR, MS, and by comparison with the literature. Compounds 1–2, 6–7, 11–12, 14, and 17–22 were firstly isolated from P. boehmeriifolium, while compounds 2, and 19–20 were isolated from Piper genus for the first time. The chemotaxonomic significance of these isolated compounds is discussed.     

Phytochemical and chemotaxonomic study on Dictamnus angustifolius G. Don ex Sweet (Rutaceae)

A phytochemical investigation of Dictamnus angustifolius led to the isolation of 14 compounds, including six furoquinoline alkaloids (1–6), two sesquiterpenoids (7, 8) and six flavonoids (9–14). The structures of these compounds were identified by spectroscopic methods and a comparison of their data with those reported in the literature. This is the first report of three furoquinoline alkaloids 1–3 and six flavonoids 9–14 from the genus Dictamnus and the first isolation of compounds 4–8 from D. angustifolius. The chemotaxonomic significance of furoquinoline alkaloids and sesquiterpenoids has also been summarized.     

Alkaloids of Toddalia asiatica (Rutaceae)

Phytochemical investigation of the alkaloidal extract of the roots of Toddalia asiatica led to the isolation of a new seco-benzophenanthridine alkaloid (1) and twelve known alkaloids (2–13). The new structure was elucidated by means of spectroscopic analysis, and the known alkaloids were identified by comparison with the literature. Among these alkaloids, 1 and 5–7 were reported from the genus Toddalia for the first time. The distribution of the isolated alkaloids at genus/family level was presented via network analysis and their chemotaxonomic significance was also discussed.     

Isolation,leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis

Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (–)-cassine (1), (–)-spectaline (2), (–)-3-O-acetylcassine (3), and (–)-3-O-acetylspectaline (4) were isolated from Senna spectabilis flowers. These compounds (1/2 and 3/4) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis. In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands 1–4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC₅₀ 15.81?μg?mL^?1) was the most effective against L. amazonensis. Compounds 2 and 4, with larger side chain, were more effective against the parasite than compounds 1 and 3. The cell viability test on Vero cells revealed that compound 2 (CC₅₀ 66.67?μg?mL^?1) was the most toxic. The acetyl group in the 3-O position of the parent structures reduced the leishmanicidal activity and the toxicity of the alkaloids. Further, molecular docking suggested that Asn143 is essential for arginase to interact with (–)-spectaline-derived compounds, which agreed with the IC₅₀ measurements. Our findings revealed that S. spectabilis is an important source of piperidine alkaloids with leishmanicidal activity. Moreover, the natural compound 3 has been isolated for the first time. Experimental investigation combined with theoretical study advances knowledge about the enzyme binding site mode of interaction and contributes to the design of new bioactive drugs against Leishmania infection.     

Five new alkaloids from Aconitum apetalum (Ranunculaceae)

Twenty-one alkaloids, including five new ones, acoapetaldines A–E (1–5), were isolated from the whole plants of Aconitum apetalum. Among them, 1 is an aconitine-type diterpenoid alkaloid, 2 and 3 are aporphine alkaloids and 4 and 5 are napelline-type diterpenoid alkaloids. The structures of the new alkaloids were elucidated by spectroscopic data analysis and that of acoapetaldine D (4) was confirmed by single crystal X-ray crystallography. Acoapetaldine A (1) and aconorine (12) exhibited moderate anti-tobacco mosaic virus (anti-TMV) activity, while corydine (15) displayed moderate antimicrobial activity against Pseudomonas aeruginosa.     

Isoquinoline alkaloids isolated from three Guatteria species

The chemical investigation of the aerial parts of Guatteria ferruginea collected in the National Park of Serra dos Órgãos, Teresópolis, Brazil and of Guatteria latifolia and Guatteria sellowiana collected in the National Park of Itatiaia, Itatiaia, Brazil resulted in the isolation and identification of six isoquinoline alkaloids, two aporphine alkaloids 3-hydroxy-nornuciferine (1), nornuciferine (2) and four oxoaporphine alkaloids lysicamine (3), isomoschatoline (4), liriodenine (5) and O-methylmoschatoline (6). The isoquinoline alkaloids were found in the species G. ferruginea, G. latifolia and G. sellowiana for the first time and they support the taxonomic position within the genus Guatteria. Isoquinoline alkaloids (5–6) can be considered chemotaxonomic markers of the subfamily Annonoideae.     

Chemical constituents from Stenosolenium saxatile (Pall.) Turcz. (Boraginaceae)

Chemical investigation on the whole plants of Stenosolenium saxatile led to the isolation of three naphthoquinones (1–3), five pyrrolizidine alkaloids (PAs) (4–8), and six phenolic acids (9–14). The structure of the isolated compounds was elucidated by different spectrometric methods (¹H NMR, ¹³C NMR and ESI-MS). These results are the first chemical data on constituents of this genus. The chemotaxonomic relationships between the genera Stenosolenium, Onosma, Arnebia, Echium and Lithospermum are also discussed.     

Anti-HBV active constituents from Piper longum

In the screening search for Hepatitis B virus inhibitory agents from medicinal plants, the ethanol extract of Piper longum Linn. was found to possess superior anti-HBV activity in vitro. Bioassay-guided fractionation coupled with repeated purification resulted in the isolation of four new compounds, involving two new glycosides longumosides A (1) and B (2) and two new amide alkaloids erythro-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (3), threo-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (4), as well as two compounds 3β,4α-dihydroxy-2-piperidinone (5), 5,6-dihydro-2(1H)-pyridinone (6) from natural source for the first time. The structures of the four new compounds were determined by extensive analyses of the MS, IR, 1D and 2D NMR data. Besides, the compounds 2–6, together with the known compounds 7–11 obtained previously, were assayed for their anti-HBV activity by using Hep G 2.2.15 cell line in vitro. Results suggested the compound piperine (7) possessed remarkable inhibitory HBV activity, against the secretion of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) with the Selectivity Index (SI) values of 15.7 and 16.8, respectively.     

Phytochemical and chemotaxonomic study on Evodia rutaecarpa var. officinalis

Phytochemical investigations of the dried and nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth. var. of officinalis (Dode) Huang (family Rutaceae) led to the isolation of twenty compounds, including eight quinolone alkaloids (1–8), seven indole quinazoline alkaloids (9–15), two limonoids (16–17) and three sterols (18–20). The chemical structures of these compounds were elucidated by extensive spectroscopic analyses and by comparison with the literature data. Notably, seven compounds (1, 3, 7, 11 and 13–15) were reported from this species for the first time, and the chemotaxonomic significance of these compounds was discussed.     

Chemical constituents of sponge Pseudoceratina sp. and their chemotaxonomic significance

The chemical investigation of Pseudoceratina sp. led to the isolation of six compounds including tyrosine brominated isoxazoline alkaloids (1 and 2), polyketide (3), and 5α,8α-epidioxysterols (4–6). The structures of these compounds were identified by comparison of NMR and MS spectroscopic data with those previously reported. Compounds 3–6 were isolated for the first time from sponges of the genus Pseudoceratina. The chemotaxonomic significance of these compounds was discussed.     

Oxytrofalcatins A–F,N-benzoylindole analogues from the roots of Oxytropis falcata (Leguminosae)

Indole alkaloids, oxytrofalcatins A–F (1–6), together with five other known alkaloids (7–11), were isolated from the roots of Oxytropis falcata. Their structures were elucidated by comprehensive spectroscopic analyses, including using 1D and 2D NMR spectroscopy and mass spectrometry. This is the first report of N-benzoylindoles from a natural source. Compounds 1–6 lacked significant cytotoxicity against SGC-7901 and HL-60 tumor cell lines.     

Chemotaxonomic significance of sesquiterpenes and amide derivatives from Chloranthus angustifolius Oliv.

Phytochemical investigation of the aerial parts of Chloranthus angustifolius Oliv. (Chloranthaceae) resulted in the isolation and characterization of seven sesquiterpenes (1–7) and six amide derivatives (8–13). All structures were established based on analysis of their spectroscopic data. This is the first report of compounds 2 and 8–13 from the family Chloranthaceae, and the first report of compounds 3–5 from C. angustifolius. Moreover, the chemotaxonomic significance of these compounds was summarized.     

Chemical constituents from the calyces of Physalis alkekengi var. franchetii

One new monoterpenoid glycoside (1), together with seven known compounds, including two alkaloids (2–3), three phenylpropanoids (4–6), and two nucleosides (7–8) were isolated from the calyces of Physalis alkekengi var. franchetii. Their structures were elucidated by a combination of detailed spectroscopic analyses, chemical methods, and comparison with reported data. These eight compounds were isolated for the first time from the genus Physalis. The chemotaxonomic significance of these compounds was summarized.     

Chemical constituents from the tubers of Pinellia ternata (Araceae) and their chemotaxonomic interest

This work describes the isolation and characterization of twenty compounds from the tubers of Pinellia ternata (Thunb.) Breit, including 17 lignanoids (1–17) and three alkaloids (18–20). All structures were established based on analysis of their spectroscopic data. It is the first report of compounds 3–11 and 13–18 from the genus Pinellia, and the first report of compounds 3–4, 6–9, 11 and 13–18 from the family Araceae. In addition, the biosynthetic pathways of the 17 lignanoids are summarized. A liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOFMS/MS) method in both positive and negative ion mode was also used to confirm the identity of these seventeen lignanoids from the tubers of P. ternata. The results from the present work provide further information about the diversity of compounds in the genus Pinellia.