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Human platelets contain conventional (α and β) and novel isoforms of PKC (δ and θ), and PKC activation can result in platelet aggregation and secretion reaction that are important for thrombus formation. Several tumor-promoting Euphorbiaceae diterpenes are known to act as direct activators of PKC, but many types of such diterpenes have not been studied as platelet stimulators. In the present study, two new and five known phorbol esters were isolated from Euphorbia grandicornis. Two of the isolated phorbol esters together with compounds representing ingenane, jatrophane, and myrsinane structural types were studied on PKC activation and platelet stimulation. The investigated phorbol esters and ingenane esters induced blood platelet aggregation and ATP secretion. PKC activation was demonstrated by inducing membrane translocation of PKCs, phosphorylation of PKC substrates, and activation of PKC signaling pathways. The PKC-activating effect of the compounds correlated well with their efficacy to cause platelet stimulation. Moreover, by using an isoform-specific PKC inhibitor, it was found that besides conventional PKCs novel PKCs also play a positive role in platelet activation caused by phorbol/ingenane esters, especially in regulating platelet aggregation. The present results suggest that platelets afford a useful model for studying PKC activators of natural origin or their chemical derivatives.

GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A–S (1–19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata. The compounds were assayed on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cells. Blocking activity on GIRK channels was exerted by 13 compounds (61–83% at 10 μM), and, among them, five possessed low potency on the hERG channel (4–20% at 10 μM). These selective activities suggest that myrsinane-related diterpenes are potential lead compounds for the treatment of atrial fibrillation.

Two new arylbenzofuran-type neolignans, 1″-dehydroegonol 3″-methyl ether (1) and egonol 3″-methyl ether (2), and four known lignan derivatives, namely, helioxanthin (3), (7E)-7,8-dehydroheliobuphthalmin (4), heliobuphthalmin (5), and 7-acetoxyhinokinin (6), were isolated from a chloroform-soluble partition of the methanol extract of the fresh roots of Heliopsis helianthoidesvar. scabra. These six compounds were evaluated in vitro in terms of their ability to inhibit the various steps involved in brain tumor metastasis formation. Compounds 3and 4inhibited the migration of both melanoma and brain endothelial cells, and 3also reduced the adhesion of melanoma cells to the brain endothelium. Furthermore, 3and 4additionally enhanced the barrier function of the blood-brain barrier and the expression of the tight junction protein ZO-1 at the junctions of the endothelial cells. These findings suggest that 3and 4may have the potential to interfere with different steps of brain metastasis formation and to enhance the barrier function of cerebral endothelial cells.

The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous N-acylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2′-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2′-methylbutylamide (4), were identified from Heliopsis helianthoidesvar. scabra. Compounds 2–4are new natural products, while 1was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii(Maca). N-Methylbutylamide 4and N-benzylamide 7showed submicromolar and selective binding affinities for the cannabinoid CB1receptor (Kivalues of 0.31 and 0.48 μM, respectively). Notably, compound 7also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50= 4 μM) and a potent inhibition of anandamide cellular uptake (IC50= 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Zdouble-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.

Five new sesquiterpenes, neurolobatin A (1), neurolobatin B (2), 5β-hydroxy-8β-isovaleroyloxy-9α-hydroxycalyculatolide (3), 3-epi-desacetylisovaleroylheliangine (4), and 3β-acetoxy-8β-isovaleroyloxyreynosin (5), were isolated from the aerial parts of Neurolaena lobata. The structures were established by means of a combined spectroscopic data analysis, including ESIMS, APCI-MS, and 1D- and 2D-NMR techniques. Neurolobatin A (1) and B (2) are unusual isomeric seco-germacranolide sesquiterpenes with a bicyclic acetal moiety, compounds 3and 4are unsaturated epoxy-germacranolide esters, and compound 5is the first eudesmanolide isolated from the genus Neurolaena. The isolated compounds (1–5) were shown to have noteworthy antiproliferative activities against human tumor cell lines (A2780, A431, HeLa, and MCF7). The anti-inflammatory effects of 1–5, evaluated in vitro using LPS- and TNF-α-induced IL-8 expression inhibitory assays, revealed that all these compounds strongly down-regulated the LPS-induced production of IL-8 protein, with neurolobatin B (2) and 3-epi-desacetylisovaleroylheliangine (4) being the most effective.

A new aconitane alkaloid, 1-O-demethylswatinine (1), was isolated from the root of Aconitum moldavicum together with the known compounds cammaconine (2), columbianine (3), swatinine (4), gigactonine (5), delcosine (6), lycoctonine (7), and ajacine (8). The structures were established by means of HRESIMS, 1D and 2D NMR spectroscopy, including 1H-1H COSY, NOESY, HSQC, and HMBC experiments, resulting in complete 1H-NMR chemical shift assignments for 1-4. The effects of the isolated compounds 4-8, together with eighteen other Aconitum diterpene and norditerpene alkaloids with different skeletal types and substitution patterns, were studied on Nav 1.2 channels by the whole-cell patch clamp technique, using the QPatch-16 automated patch clamp system. Pyroaconitine, ajacine, septentriodine, and delectinine demonstrated significant Nav 1.2 channel inhibition (57-42%) at 10 μM concentration; several other compounds (acovulparine, acotoxicine, hetisinone, 14-benzoylaconine- 8-O-palmitate, aconitine, and lycoctonine) exerted moderate inhibitory activity (30-22%), while the rest of the tested alkaloids were considered to be inactive. On the basis of these results and by exhaustive comparison of data of previously published computerized QSAR studies on diterpene alkaloids, certain conclusions on the structure-activity relationships of Aconitum alkaloids concerning Nav 1.2 channel inhibitory activity are proposed. [ABSTRACT FROM AUTHOR]

Phytochemical study of whole, undried plants of Euphorbia esulaled to the isolation of six new (1–6) jatrophane diterpene polyesters, named esulatins H–M, together with the known compounds 2α,3β,5α,7β,15β-pentaacetoxy-9α-nicotinoyloxyjatropha-6(17),11-dien-14-one (7), salicinolide (8), and euphosalicin (9). The structures and relative configuration of 1–6were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. All these compounds, together with diterpenes (10–14) isolated previously from this plant, were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 cells. The multidrug-resistance-reversing activities were also investigated on L5178 mouse lymphoma cells transfected with the pHa MDR1/A retrovirus DNA. Preliminary structure–activity relationship data are discussed.

Extensive chromatographic purification of the alkaloid fraction of Aconitum vulparia Rchb. led to the isolation of a new norditerpene alkaloid, vulparine (1), besides the known compounds septentriodine (2), finetiadine (3), anthranoyllycoctonine (4), N-methyl-N-deethyllycoctonine (5) and delectinine (6). The structure of the new compound was determined by means of HRMS, 1D and 2D NMR spectroscopy. Detailed NMR studies, including 1H-1H COSY, NOESY, HSQC and HMBC experiments, resulted in complete and unambiguous 1H chemical shift assignments for 2 and 6, and revision of some 13C NMR data. Compounds 1 - 4 were evaluated for their cytotoxic activities, and 1, 3 and 4 were found to exhibit marginal cell growth inhibitory activity against breast adenocarcinoma (MCF-7) and cervix adenocarcinoma (HeLa) cells.

Acotoxinine (1), a new norditerpene alkaloid, was isolated from the roots of Aconitum toxicumRchb., together with the structurally related C19 diterpene alkaloids neoline (2) and aconitine (3) and C20 diterpene alkaloids songorine (4) and songoramine (5). The structures were elucidated by HR-MS and advanced NMR methods, including 1H-NMR, JMOD, 1H,1H-COSY, HSQC, and HMBC experiments. This is the first report of C20 diterpenoid alkaloids in Aconitum toxicum.

Three new, highly functionalized jatrophane diterpenes (1–3) have been isolated from the whole, dried plants of Euphorbia platyphyllos L., together with one known jatrophane polyester (4). The structures were established by UV/VIS spectroscopy, HR-ESI-MS, and advanced two-dimensional NMR, including ¹H-NMR, JMOD, ¹H,¹H-COSY, HMQC, and HMBC experiments. Stereochemical studies and conformational analyses were performed by means of NOESY experiments. Interestingly, compounds 1–4 do not represent a stereochemically uniform series because they differ in the orientations of the Me groups at C(2), C(6), and C(13). A similar observation was reported earlier for Euphorbia serrulata, whose diterpenes are related to the compounds obtained from E. platyphyllos. This chemical relationship is of taxonomic importance and supports the botanical similarity of the two species.

The term lipo-alkaloid is used for C19aconitane alkaloids containing one or two long-chain fatty acid residues. Lipo-alkaloids are transesterified derivatives of the most toxic and highly effective diester-type diterpene alkaloids, such as aconitine, hypaconitine, mesaconitine. Lipo-alkaloids are native minor compounds of aconite drugs, but their amount significantly increases after traditional processing, which is a general method in the Far Eastern traditional medicinal systems. Analytical works demonstrated that cautious processing (usually boiling) of crude aconite roots decreases the amount of normal diterpene alkaloids and increases the concentration of lipo-alkaloids resulting in the reduction of toxicity of the drugs. Many papers reported that lipo-alkaloids occur as a complex mixture in the drugs, and the isolation of the individual components is extremely difficult. These compounds have been identified using highly sensitive analytical methods (HPLC-MS, NMR), and semisynthetic approaches have been developed to ensure lipo-alkaloids in pure form for pharmacological studies.This review summarizes the structure, chemistry, semisynthesis, analytics and bioactivities of lipo-alkaloids. On the basis of 32 references this is the first comprehensive study on this topic, covering the data of 173 compounds.

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