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Magnoflorine is an aporphine alkaloid present in plant species belonging to the Berberidaceae, Magnoliaceae, Menispermaceae, or Papaveraceae botanical families. The interest of magnoflorine has increased recently due to its multiplicity of pharmacological properties. The aim of this study was the analysis of combined anti-proliferative effect of magnoflorine and cisplatin and the assessment of drug&ndash, drug pharmacological interaction between these agents using isobolographic method in MDA-MB-468 human breast, NCIH1299 lung, TE671 rhabdomyosarcoma, or T98G glioblastoma cancer cell lines. Magnoflorine in combination with cisplatin at a fixed ratio of 1:1 augmented their anticancer action and yielded synergistic or additive pharmacological interactions by means of isobolographic method, therefore combined therapy using these two active agents can be a promising chemotherapy regimen in the treatment of some types of breast, lung, rhabdomyosarcoma, and glioblastoma cancers.

Boldine is the main alkaloid of Peumus boldus Molina, widely used in the traditional medicine for the treatment of digestive disorders. It is a compound with excellent antioxidant and anti-inflammatory properties already described. Despite the widespread use of P. boldus for digestive disorders treatment, the gastroprotective effect of Boldine remains unknown. Considering the need for new approaches to treat gastric ulcers with fewer side effects than current therapy, this study aimed to investigate the gastroprotective effect of Boldine in mice, as well as the mechanisms underlying this effect. The gastroprotective effect of Boldine was evaluated on gastric ulcer induced by 60% ethanol/0.3 M HCl or indomethacin (100 mg/kg) in mice. Histological analysis and the mucin-like glycoprotein content were evaluated in ethanol-ulcerated tissue, as well as, oxidative stress and inflammatory parameters. The mechanisms involved in the effect of Boldine were evaluated by pretreating mice with NEM (a sulfhydryl group chelator, 10 mg/kg, i.p.), l -NAME (a non-selective nitric oxide synthase inhibitor, 70 mg/kg, i.p.), yohimbine (an alpha-adrenergic receptor antagonist, 2 mg/kg, i.p.) and indomethacin (a cyclooxygenase inhibitor, 10 mg/kg, i.p.). In addition, the in vitro effect of Boldine on H+/K+-ATPase activity was determined. Boldine was able to protect gastric mucosa against the damage induced by ethanol/HCl and indomethacin, as evidenced by reduced lesion area and histological analysis. Moreover, the alkaloid reduced oxidative stress and inflammatory mediators in ethanol-ulcerated tissue, beyond has increased mucin-like glycoprotein amount. Finally, Boldine effect is dependent on non-protein sulfhydryl groups and prostanoids but does not involve the inhibition of H+/K + -ATPase activity, being a promising natural resource for gastric ulcer treatment.

During periodontitis, tooth-supporting alveolar bone is resorbed when there is an increased expression of the pro-osteolytic factor termed receptor activator of nuclear factor κB ligand (RANKL), which is responsible for osteoclast differentiation and activation. In periodontitis-affected tissues, the imbalance between T-helper type-17 (Th17) and T-regulatory (Treg) lymphocyte activity favors this RANKL overexpression. In this context, immunotherapeutic strategies aimed at modulating this Th17/Treg imbalance could eventually arrest the RANKL-mediated alveolar bone loss. Boldine has been reported to protect from pathological bone loss during rheumatoid arthritis and osteoporosis, whose pathogenesis is associated with a Th17/Treg imbalance. However, the effect of boldine on alveolar bone resorption during periodontitis has not been elucidated yet. This study aimed to determine whether boldine inhibits alveolar bone resorption by modulating the Th17/Treg imbalance during periodontitis.Mice with ligature-induced periodontitis were orally treated with boldine (10/20/40 mg/kg) for 15 consecutive days. Non-treated periodontitis-affected mice and non-ligated mice were used as controls. Alveolar bone loss was analyzed by micro-computed tomography and scanning electron microscopy. Osteoclasts were quantified by histological identification of tartrate-resistant acid phosphatase-positive cells. Production of RANKL and its competitive antagonist osteoprotegerin (OPG) were analyzed by ELISA, quantitative polymerase chain reaction (qPCR), and immunohistochemistry. The Th17 and Treg responses were analyzed by quantifying the T-cell frequency and number by flow cytometry. Also, the expression of their signature transcription factors and cytokines were quantified by qPCR.Boldine inhibited the alveolar bone resorption. Consistently, boldine caused a decrease in the osteoclast number and RANKL/OPG ratio in periodontal lesions. Besides, boldine reduced the Th17-lymphocyte detection and response and increased the Treg-lymphocyte detection and response in periodontitis-affected tissues.Boldine, administered orally, inhibited the alveolar bone resorption and modulated the Th17/Treg imbalance during experimental periodontitis.

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Introduction Lauraceae alkaloids are a structurally diverse class of plant specialised secondary metabolites that play an important role in modern pharmacotherapy, being useful as well as model compounds for the development of synthetic analogues. However, alkaloids characterisation is challenging due to low concentrations, the complexity of plant extracts, and long processes for accurate structural determinations. Objective The use of high-performance thin layer chromatography coupled with desorption electrospray ionisation multistage mass spectrometry (HPTLC DESI-MSn ) as a fast tool to identify alkaloids present in Ocotea spixiana extract and evaluate the extract's acaricide activity. Methods Ocotea spixiana twigs were extracted by conventional liquid-liquid partitioning. HPTLC analysis of the ethyl acetate extract was performed to separate isobaric alkaloids prior to DESI-MSn analysis, performed from MS3 up to MS7 . The extract's acaricide activity against Rhipicephalus microplus was evaluated by in vitro (larval immersion test) and in silico tests. Results HPTLC-DESI-MSn analysis was performed to identify a total of 13 aporphine and four benzylisoquinoline-type alkaloids reported for the first time in O. spixiana. In vitro evaluation of the extract and the alkaloid boldine showed significant activity against R. microplus larvae. It was established in silico that boldine had important intermolecular interactions with R. microplus acetylcholinesterase enzyme. Conclusion The present study demonstrated that HPTLC-DESI-MSn is a useful analytical tool to identify isoquinoline alkaloids in plant extracts. The acaricide activity of the O. spixiana ethyl acetate extract can be correlated to the presence of alkaloids.

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Roemerine is a naturally occurring aporphine alkaloid. In this study, we screened a conformer library of Food and Drug Administration (FDA)-approved drugs to identify similar drugs that can assist in identifying the biological targets of roemerine. To assess the neuroactivity in vitro, we measured the levels of cell metabolites, Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HT) in SH-SY5Y cell line. By means of structure-based virtual screening, we identified five drugs that are similar to roemerine; mirtazapine, atomoxetine, epinastine, diphenhydramine and orphenadrine. GC-MS metabolomics study revealed that roemerine has a high impact on alanine-aspartate-glutamate pathway in cell lysate and cultured medium. Additionally, roemerine increased intercellular 5-HT level and intracellular BDNF protein expression at 10 µM. In conclusion, roemerine — a major alkaloid in antidepressant-like effect possessing plants (P. lacerum and P. syriacum) — has a neuronal activity through increasing BDNF protein expression and affecting serotonergic and glutamatergic systems in SH-SY5Y cell line.

A traceless approach to quinolin-4(1H)-one scaffolds through Rh(III)-catalyzed redox-neutral [3+3] cyclization of N-nitrosoanilines with cyclopropenones has been achieved. This protocol features short reaction time and atom-economical combination without extra additives, which can be further applied in the construction of privileged heterocyclic compounds in pharmaceutical chemistry.

Obesity, is an increasingly global public health problem associated complications. However, the proven anti-obesity agents are inefficient with adverse side effects; hence attention is being paid to novel drugs from natural resources to manage obesity and obesity-related diseases. Nuciferine (NF) is a high-quality aporphine alkaloid present in lotus leaf. Unlike the chemical drugs, NF elicits anti-obesity, anti-dyslipidemia, anti-hyperglycemic, anti-hypouricemic, anti-inflammatory, and anti-tumor effects, and affinity to neural receptors, and protection against obesity-related diseases. The underlying mechanism of NF includes the regulation of targeted molecules and pathways related to metabolism, inflammation, and cancer and modulation of Ca2+ flux, gut microbiota, and ferroptosis. Besides, the clinical application, availability, pharmacokinetics, pharmaceutics, and security of NF have been established, highlighting the potential of developing NF as an anti-obesity agent. Therefore, this review provides a comprehensive summarization, which sheds light on future research in NF.

The current study was designed to explore the underlying therapeutic effect of berberine (BBR), an alkaloid compound against LPS (1 μg/ml)/TNFα (10 ng/ml) mediated apoptosis signal-regulating kinase 1 (ASK1) signaling in RAW 264.7 macrophages and adjuvant-induced arthritic synovial macrophages (AA-SM) with relation to miR-23a levels. LPS and TNFα stimulation abrogated the expression of miR-23a resulting in TLR4/TRAF2 mediated ASK1 activation and downstream phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). BBR (25–75 μM) treatment ameliorated the gene expression levels of TLR4, TRAF2, TNFα, IL-6, and IL-23 through the upregulation of miR-23a. Subsequently, BBR suppressed the levels of TLR4/TRAF2 mediated phosphorylation of ASK1/p38 and attenuated the expression of various pro-inflammatory cytokines (TNFα, IL-6 & IL-23) in RAW 264.7 macrophages and AA-SM cells. BBR was able to counteract these factors through activation of miR-23a levels in LPS/TNFα stimulated RAW 264.7 macrophages and AA-SM cells. NQDI1 (30 μM) treatment inhibited ASK1 activation resulting in basal levels of miR-23a, owing to the conclusion that ASK1 activation downregulates miR-23a levels inside the cells. Overall, our current findings predict that BBR is a potential candidate for therapeutic targeting of TLR4/TRAF2 mediated ASK1 activation in inflammatory and in RA pathogenesis possibly through post-transcriptional gene silencing via upregulation of miR-23a.

Objective To investigate efficacy of Chinese medicine magnoflorine combined with hyaluronic acid (HA)-gel in promoting subchondral bone (SCB) regeneration and attenuating cartilage degeneration in early osteoarthritis (OA). Methods MC3T3-E1 under magnoflorine treatment was assayed by XTT to determine cell viability. Cell proliferation was reflected through cell cycle. Osteoblast mineralization was stained by Alizarin Red. Standardized bone canal of 1 mm in diameter and 4 mm in depth was made on tibial medial plateau of 4-month-old Dunkin-Hartley spontaneous knee OA guinea pigs. Guinea pigs (n = 5/group) were treated once intra-bone canal injection of 2 μl HA-gel, 2 μl HA-gel+50 ng magnoflorine and null (Defect) respectively, except sham group. The left hind limbs were harvested for μCT scan and histopathological staining 2-month post-surgery. Results 25 μg/ml magnoflorine treatment significantly increased cell viability, S-phase and mineralization of MC3T3-E1 cells. In vivo, HA-gel + magnoflorine treatment significantly altered SCB microstructure; changes included increase in bone volume fraction (BV/TV), trabecular number (Tb.N), connectivity density (Conn.Dn), and decrease in degree of anisotropy (DA), which implied trabecular bone regeneration. Treatment also resulted in a decrease in modified Mankin's scores, and an increase in volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and fractal dimension (FD, roughness indicator of osteochondral conjunction), compared to Defect and HA groups. Furthermore, FD was positively associated with volume ratio of HC/CC and negatively associated with modified Mankin's scores. Finally, histological results showed that due to a faster regeneration of SCB with the HA-gel + magnoflorine treatment, the reduction of cartilage matrix and the decreased expression of chondrogenic signals were attenuated. Conclusion Our study elucidated the potential benefits of HA-gel + magnoflorine in promoting SCB regeneration and revealed a protective effect of stimulating recovery of the SCB integrity on attenuating cartilage degradation to prevent OA progression.

Aporphine alkaloids, characterized by a heterocyclic aromatic basic skeleton, are known from different organisms and exhibit various biological activities: anti-tumor, anti-viral, anti-microbial, anti-inflammatory etc. The review gives information which provides an overview of the latest progress in the structural diversity and the biological activity of the aporphine alkaloids with their derivatives isolated from natural resource in recent years. Additionally, the synthetic approaches of aporphine alkaloids have also been reviewed.

Objectives To assess the antiplasmodial activity of the ethanol extract of Xylopia sericea leaves, Annonaceae, often associated with antimalarial use and to perform a bioguided isolation of active compounds. Methods Dereplication of ethanol extract by the UPLC-DAD-ESI-MS/MS technique allowed the identification of the major constituents, isolation and identification of alkaloids. The antiplasmodial and cytotoxic activity of the extract, fractions and isolated compounds was evaluated against the chloroquine-resistant W2 strain Plasmodium falciparum and HepG2 cells, respectively. Key findings Ethanol extract showed high reduction of parasitemia as well as moderate cytotoxicity (86.5 ± 3.0% growth inhibition at 50 μg/ml and CC50 72.1 ± 5.1 μg/ml, respectively). A total of eight flavonoids were identified, and two aporphine alkaloids, anonaine and O-methylmoschatoline, were isolated. Anonaine disclosed significant antiplasmodial effect and moderate cytotoxicity (IC50 23.2 ± 2.7 μg/ml, CC50 38.3 ± 2.3 μg/ml, SI 1.6) while O-methylmoschatoline was not active against P. falciparum and showed a low cytotoxicity (33.5 ± 1.9% growth inhibition at 50 μg/ml, CC50 274.4 ± 0.5 μg/ml). Conclusions Characterization of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS as well as its antiplasmodial activity and the occurrence of anonaine and O-methylmoschatoline in this Xylopia species are reported by the first time.

Three undescribed aporphine alkaloids laurodionine B (1), illigerine A (2), and N-formyl-laurolitsine (3) were isolated from the methanolic extracts of the Chinese medicinal plant, Illigera aromatica, together with three known analogues (4–6). The chemical structures of 1–6 were identified by spectroscopic methods including 1D and 2D NMR (1H, 13C, COSY, HSQC, and HMBC) and high resolution mass spectrometry (HRESIMS). Compounds 1–3 showed moderate inhibitory activities in vitro against two cultured tumor cell lines, Hela and SMMC7721, with IC50 values of 32.42–62.90 μM. Only compound 1 had in vitro cytotoxic activity against Bcap37 cells, with the IC50 value of 90.61 μM.

Boldine is a natural antioxidant that exhibits some important pharmacological properties, which is due to its free radical scavenging effects. And at the same time, reactive oxygen species (ROS) has an important role in pathogenesis of seizure; hence, reducing it via antioxidants like boldine seems to be effective in treating seizure. This study was designed to investigate whether acute treatment with boldine could alter seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated to see if boldine’s antioxidant properties play a role in its anti-convulsant activity. Boldine acute administration increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole model. Moreover, boldine increased seizure threshold induced by intravenous infusion of pentylenetetrazole. Additionally, acute doses of boldine reduced the duration of tonic hind-limb extension in the electroshock-induced seizure model. Non-effective dose of vitamin C (as an antioxidant agent) and boldine had anti-convulsant effect in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole and electroshock models. Boldine administration increased glutathione and superoxide dismutase levels in mice whole brain. The result showed boldine anti-seizure properties, which might be due to its antioxidant activity.

The natural aporphine alkaloids including crebanine (CN), O-methylbulbocapnine (OMP), and dicentrine (DC), and protoberberine alkaloids, tetrahydropalmatine (THP) and N-methyl tetrahydropalmatine (NTHP), have been found in Stephania venosa. Previous reports demonstrated CN and THP exhibited anti-inflammatory properties. In this study, we investigated anti-inflammatory effect of CN analogs including OMP, DC, THP, and NTHP in RAW264.7 macrophages. The pre-treatment of macrophages with CN, OMP and DC suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators including interleukin-6 (IL-6), tumor necrosis factor alpha, prostaglandin E2 and nitric oxide, in which the rank-order of inhibitory potency was DC>CN≥OMP. Whereas, high dose THP (30-40 µg/mL) reduced LPS-induced IL-6 production in RAW264.7 cells but NTHP did not effect. Moreover, CN, OMP and DC inhibited the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2. OMP and DC inhibited LPS-induced nuclear factor kappa B (NF-κB) activation by suppressing the phosphorylation of NF-κB at Ser536, but not the nucleus translocation and inhibitor of kappaB (IκB)-α degradation. In addition, OMP and DC also reduced the phosphorylation and nucleus translocation of activator protein-1 (AP-1). Furthermore, OMP and DC suppressed the LPS-activated myeloid differentiation factor 88 (MyD88), Akt and mitogen-activated protein kinases (MAPKs) signaling pathway, which were the upstream signaling regulators of AP-1 and NF-κB. Collectively, OMP and DC have an anti-inflammatory effect on RAW264.7 macrophages by the suppression of pro-inflammatory cytokines and mediators. The inhibitory property of OMP and DC is mediated by blockage the activation of MyD88, MAPKs, Akt, NF-κB and AP-1 signaling molecules.

Nine new isoquinoline alkaloids, including two proaporphine (1–2), three aporphine (3–5), two oxoaporphine (6–7), and two seco-bisbenzylisoquinoline (8–9), together with three known alkaloids (10−12) were isolated from the whole plant of Thalictrum wangii. Their structures were established on the basis of spectroscopic data. The antitumor activities of the isolated compounds were evaluated in vitro against glioma stem cells. Compounds 3–8 showed the cytotoxicity with IC50 values 15–20 μg/mL.

Eighteen alkaloids were detected in the bark, leaves, wood and roots of Peumus boldus, including traces of secoboldine, N-methylsecoboldine (boldine methine), glaucine and norreticuline, not reported previously as constituents of this species. Using appropriate standards, we quantified thirteen of them by UHPLC-MS/MS. Boldine was dominant in the bark, and laurolitsine in wood and roots. The alkaloid composition of the leaves, determined for 130 individually identified trees, classified by age and sex, was highly variable, where N-methyllaurotetanine, laurotetanine, coclaurine and in some cases isocorydine predominated, but not boldine.

Background A quality marker (Q-marker) is defined as an inherent chemical compound that is used for the quality control of a drug. Its biological activities are closely related to safety and therapeutic effects. Generally, a multiple-component herbal medicine may have many Q-markers. We therefore proposed a concept of “super Q-marker” satisfying both the criterion of Q-markers and PK-markers to be used in more effective quality control of herbal medicine. Purpose The first aim was to find suitable prototype-based PK-markers from Tangzhiqing tablets (TZQ), a Chinese patent medicine. Then super Q-markers were expected to be identified from the prototype-based PK-markers based on an in vitro-in vivo correlation study. Methods Potentially eligible prototype-based PK-markers were identified in a single- and multiple-dose pharmacokinetic study on TZQ in 30 healthy volunteers. The in vitro dissolution and permeation profiles of the prototype-based PK-markers of TZQ were evaluated by the physiologically-based drug dissolution/absorption simulating system (DDASS). An in vitro-in vivo correlation analysis was conducted between the dissolution/permeation behaviors in DDASS and the actual absorption profiles in human to test the transferability and traceability of the promising super Q-markers for TZQ. Results In human, plasma paeoniflorin and nuciferine as prototype-based PK-markers exhibited the appropriate pharmacokinetic properties, including dose-dependent systemic exposure (AUC, Cmax) and a proper elimination half-life (1∼3h). In DDASS, it was predicted that paeoniflorin and nuciferine are highly permeable but the absorption rates are primarily limited by the dissolution rates. Moreover, the established in vitro-in vivo correlations of paeoniflorin and nuciferine were in support of the super Q-markers features. Conclusion Paeoniflorin and nuciferine are identified as the super Q-markers from the prototype-based PK-markers of TZQ based on findings from a combination of in vitro, in vivo, and in vitro-in vivo correlation studies. This method is practical for optimal identification of qualified Q-markers, thus helping improve the quality control of herbal medicines.

Malonyl-CoA:acyl carrier protein transacylase (FabD), being an essential enzyme of the FAS II pathway, is an attractive target for developing broad-spectrum antibiotics. It performs initiation reaction to form malonyl-ACP, which is a key building block in fatty acid biosynthesis. In this study, we have characterized the FabD from drug-resistant pathogen Moraxella catarrhalis (McFabD). More importantly, we have shown the binding of McFabD with three new compounds from the class of aporphine alkaloids. ITC based binding studies have shown that apomorphine is binding to McFabD with a stronger affinity (KD = 4.87 μM) as compared to boldine (KD = 7.19 μM) and magnoflorine (KD = 11.7 μM). The possible mechanism of fluorescence quenching is found to be static with Kq values higher than 1010, which was associated with the ground state complex formation of aporphine alkaloids with McFabD. Conformational changes observed in the secondary and tertiary structure marked by the loss of helical content during the course of interactions. Molecular docking based studies have predicted the binding mode of aporphine alkaloids and it is found that these compounds are interacting in a similar fashion as known inhibitor corytuberine is interacting with McFabD. The analysis of docking poses have revealed that His 210, Leu102, Gln19, Ser101 and Arg 126 are critical residues, which may play important role in binding. The growth inhibition assay has shown that apomorphine has better MIC value (4–8 μg/ml) against Moraxella catarrhalis as compared to boldine and magnoflorine. Therefore, the current study suggests that aporphine alkaloids can act as antibacterial agents and possible target of these compounds could be FabD enzyme from the FAS II pathway, and apomorphine scaffold will be more suitable among these compounds for potential development of antibacterial agents.

Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential.

Plant-derived substances have regained interest in the fight against antibiotic resistance owing to their distinct antimicrobial mechanisms and multi-target properties. With the recent advances in instrumentation and analysis techniques, OMIC approaches are extensively used for target identification and elucidation of the mechanism of phytochemicals in drug discovery. In the current study, RNA sequencing based transcriptional profiling together with global differential protein expression analysis was used to comparatively elaborate the activities and the effects of the plant alkaloids boldine, bulbocapnine, and roemerine along with the well-known antimicrobial alkaloid berberine in Bacillus subtilis cells. The transcriptomic findings were validated by qPCR. Images from scanning electron microscope were obtained to visualize the effects on the whole-cells. The results showed that among the three selected alkaloids, only roemerine possessed antibacterial activity. Unlike berberine, which is susceptible to efflux through multidrug resistance pumps, roemerine accumulated in the cells. This in turn resulted in oxidative stress and building up of reactive oxygen species, which eventually deregulated various pathways such as iron uptake. Treatment with boldine or bulbocapnine slightly affected various metabolic pathways but has not changed the growth patterns at all.

The tyrosine kinase inhibitor Sunitinib is used to treat cancer and is linked to severe adverse cardiovascular events. Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N-terminal kinase (JNK) signal transduction pathway. Apoptosis signal-regulating kinase 1 (ASK1) is the upstream activator of MKK7 and is specifically inhibited by 2,7-dihydro-2,7-dioxo-3H-naphtho[1,2,3-de]quinoline-1-carboxylic acid ethyl ester (NQDI-1). This study investigates the role of ASK1, MKK7 and JNK during Sunitinib-induced cardiotoxicity. Infarct size were measured in isolated male Sprague-Dawley rat Langendorff perfused hearts treated for 125 min with Sunitinib in the presence and absence of NQDI-1. Left ventricular cardiac tissue samples were analysed by qRT-PCR for MKK7 mRNA expression and cardiotoxicity associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) or Western blot analysis to measure ASK1/MKK7/JNK phosphorylation. Administration of Sunitinib (1 μM) during Langendorff perfusion resulted in increased infarct size, increased miR-133a expression, and decreased phosphorylation of the ASK1/MKK7/JNK pathway compared to control. Co-administration of NQDI-1 (2.5 μM) attenuated the increased Sunitinib-induced infarct size, reversed miR-133a expression and restored phosphorylated levels of ASK1/MKK7/JNK. These findings suggest that the ASK1/MKK7/JNK intracellular signalling pathway is important in Sunitinib-induced cardiotoxicity. The anti-cancer properties of Sunitinib were also assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay. Sunitinib significantly decreased the cell viability of human acute myeloid leukemia 60 cell line (HL60). The combination of Sunitinib (1 nM-10 μM) with NQDI-1 (2.5 μM) enhanced the cancer-fighting properties of Sunitinib. Investigations into the ASK1/MKK7/JNK transduction pathway could lead to development of cardioprotective adjunct therapy, which could prevent Sunitinib-induced cardiac injury.

Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress.

Two novel aporphine-derived alkaloids, aporaloids A and B (1 and 2), together with eight known biogenetically related alkaloids (3−10), two known isoquinoline alkaloids (3 and 4), and six known aporphinoid alkaloids (5–10) were isolated from the stems of Fissistigma glaucescens. Their structures were elucidated using comprehensive spectroscopic methods. Compounds 1 and 2 represent the rare example of a six-membered lactone ring aporphine-derived alkaloids from natural products. The inhibitory activities of all compounds against four cancer cell lines were evaluated. Aporaloids A and B (1 and 2) showed broad spectrum cytotoxic activities.

The incidence and prevalence of metabolic syndrome has steadily increased worldwide. As a major risk factor for various diseases, metabolic syndrome has come into focus in recent years. Some natural aporphine alkaloids are very promising agents in the prevention and treatment of metabolic syndrome and its components because of their wide variety of biological activities. These natural aporphine alkaloids have protective effects on the different risk factors characterizing metabolic syndrome. In this review, we highlight the activities of bioactive aporphine alkaloids: thaliporphine, boldine, nuciferine, pronuciferine, roemerine, dicentrine, magnoflorine, anonaine, apomorphine, glaucine, predicentrine, isolaureline, xylopine, methylbulbocapnine, and crebanine. We particularly focused on their impact on metabolic syndrome and its components, including insulin resistance and type 2 diabetes mellitus, endothelial dysfunction, hypertension and cardiovascular disease, hyperlipidemia and obesity, non-alcoholic fatty liver disease, hyperuricemia and kidney damage, erectile dysfunction, central nervous system-related disorder, and intestinal microbiota dysbiosis. We also discussed the potential mechanisms of actions by aporphine alkaloids in metabolic syndrome.

Cocaine is a naturally occurring psychostimulant drug available worldwide. Drug trafficking networks adulterate pure cocaine with cutting agents to increase their earnings. This study presents a descriptive statistical analysis of the cutting agents found in 2118 cocaine samples that were seized in the Northern Region of Colombia (in the period 2015–2017). The data used in this study was drawn from the GC-MS analytical reports of the National Institute of Legal Medicine and Forensic Sciences –Colombia, Northern Region. Results showed diverse cutting agents in seized cocaine samples, from which the most commonly used are caffeine, phenacetin, lidocaine, imidazole and levamisole. In addition, cocaine samples showed different mixtures of the above cutting agents, predominantly caffeine/phenacetin and caffeine/lidocaine/phenacetin mixtures.

Diclinanona calycina R. E. Fries popularly known as “envira”, is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of D. calycina was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in D. calycina as well as in the genus Diclinanona. The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (1), aporphine, anonaine (2), oxoaporphine, liriodenine (3), benzyltetrahydroisoquinolines, (S)-(+)-reticuline (4), dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (5), (+)-1S,2R-reticuline Nβ-oxide (6), and (+)-1S,2S-reticuline Nα-oxide (7), tetrahydroprotoberberine, coreximine (8), and pavine, bisnorargemonine (9). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (10), dichamanetin (11), and a mixture of uvarinol (12) and isouvarinol (13). Compound 5 is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (10), and the mixture of uvarinol (12) and isouvarinol (13), which presented moderate cytotoxic activity against the tested cancer cell lines (&lt, 20.0 µg·mL−1) and low cytotoxicity against the non-cancerous cell line MRC-5 (&gt, 25.0 µg·mL−1). Dichamanetin (11) showed cytotoxic activity against HL-60 and HCT116 with IC50 values of 15.78 µg·mL−1 (33.70 µmol·L−1) and 18.99 µg·mL−1 (40.56 µmol·L−1), respectively while the mixture of uvarinol (12) and isouvarinol (13) demonstrated cytotoxic activity against HL-60, with an IC50 value of 9.74 µg·mL−1, and HCT116, with an IC50 value of 17.31 µg·mL−1. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound.

Inspired by the intriguing structures and bioactivities of dimeric alkaloids, 11 new thalifaberine-type aporphine-benzylisoquinoline alkaloids, thalicultratines A-K, a tetrahydroprotoberberine-aporphine alkaloid, thalicultratine L, and five known ones were isolated from the roots of Thalictrum cultratum. Their structures were defined on the basis of NMR and HRESIMS data. The antiproliferative activities of compounds 1-17 were evaluated against human leukemia HL-60 and prostate cancer PC-3 cells. Most alkaloids showed potent cytotoxicity against selected cancer cells. Preliminary SARs are discussed. The most active new compound (3), with an IC50 value of 1.06 μM against HL-60 cells, was selected for mechanism of action studies. The results revealed that compound 3 induced apoptosis and arrested the HL-60 cell cycle at the S phase with the loss of mitochondria membrane potential. The nuclear morphological Hoechst 33258 staining assay was also carried out, and the results confirmed apoptosis.

Protein-protein interactions (PPI) are a new emerging class of novel therapeutic targets. In order to probe these interactions, computational tools provide a convenient and quick method towards the development of therapeutics. Keeping this in view the present study was initiated to analyse interaction of tumour suppressor protein p53 (TP53) and breast cancer associated protein (BRCA1) as promising target against breast cancer. Using computational approaches such as protein-protein docking, hot spot analyses, molecular docking and molecular dynamics simulation (MDS), stepwise analyses of the interactions of the wild type and mutant TP53 with that of wild type BRCA1 and their modulation by alkaloids were done. Protein-protein docking method was used to generate both wild type and mutant complexes of TP53-BRCA1. Subsequently, the complexes were docked using sixteen different alkaloids, fulfilling ADMET and Lipinski's rule of five criteria, and were compared with that of a well-known inhibitor of PPI, namely nutlin. The alkaloid dicentrine was found to be the best docked alkaloid among all the docked alklaloids as well as that of nutlin. Furthermore, MDS analyses of both wild type and mutant complexes with the best docked alkaloid i.e. dicentrine, revealed higher stability of mutant complex than that of the wild one, in terms of average RMSD, RMSF and binding free energy, corroborating the results of docking. Results suggested more pronounced interaction of BRCA1 with mutant TP53 leading to increased expression of mutated TP53 thus showing a dominant negative gain of function and hampering wild type TP53 function leading to tumour progression.

Among the existing methods for the synthesis of bioactive and/or complex small molecules, organic transformations such as C–C and C–N bond formation have been significantly developed and exploited for the synthesis of diverse synthetic and natural fused aza-polycycles. The abundance and biological and physical activities of 1-phenethyl-tetrahydroisoquinolines, aporphines, homoaporphines, and β-carbolines have inspired many organic chemists to seek sustainable and efficient protocols for their preparation. However, these methodologies involve multiple steps and in most cases the key reaction step is based on the formation of new C–C and/or C–N bonds, and this is usually the critical step that lowers the yields and selectivity. This review is focused on the advances made in recent years regarding the synthesis of these selected natural fused aza-polycycles, overviewing the substrate scope, limitations, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions, concentrating on developments from 2010 to 2016.1 Introduction2 1-Phenethyl-tetrahydroisoquinolines; Dysoxylum Alkaloids3 Aporphines, Homoaporphines, and Semisynthetic Derivatives4 Harmala and Eudistomin Alkaloids and Their Biological Properties5 Metal-Catalyzed C–C Bond Formation6 Pd-Catalyzed C–C and C–N Bond Formation7 Metal-Catalyzed C–N Bond Formation8 [4+2] Cycloaddition in the Synthesis Of Aporphines9 Tandem C–N/C–C Bond Formation: The Pictet–Spengler Reaction10 Miscellaneous Methods11 Conclusions

This study aimed to elucidate the mechanisms of nuciferine (a main aporphine alkaloid of lotus leaf extract), which can induce relaxation in contracted tracheal rings. Under Ca2+-free and 2 mM Ca2+ conditions, we found that nuciferine had no effect on the resting muscle tone of tracheal rings. In contrast, nuciferine relaxed high K+-contracted mouse tracheal rings in a dose-dependent manner and inhibited both Ca2+ influx and voltage-dependent L-type Ca2+ channel currents induced by high K+. Similarly, nuciferine also inhibited acetylcholine-induced contractions in mouse tracheal rings in a dose-dependent manner. Meanwhile, both acetylcholine-induced intracellular Ca2+ influx and whole-cell currents of nonselective cation channels were blocked by nuciferine. Together, the results indicate that nuciferine-induced relaxation in tracheal rings mainly occurred due to the inhibition of extracellular Ca2+ influx through the blockade of voltage-dependent L-type Ca2+ channels and/or nonselective cation channels. These results suggest that nuciferine has a therapeutic effect on respiratory diseases associated with the aberrant contraction of airway smooth muscles and/or bronchospasm.