Bioactive alkaloids from Nepalese Corydalis chaerophylla D.C. acting on the regulation of PCSK9 and LDL-R in vitro.

Four new alkaloids Chaeronepaline-A (1), Chaeronepaline-B (2), Chaeronepaline-C (3), and Chaeronepaline-D (4) were isolated from Corydalis chaerophylla D.C. collected from Nepal and their structures were elucidated by spectroscopic data, 1D, 2D NMR and mass spectrometry. The structures were established as 3,12- Dimethoxy-5,6-dihydroisoquinolino [2,1-b] isoquinolin- 7- ium- 2, 9- diol (1), 7-methyl-5, 6, 7, 8-tetrahydroisoquinoline- 2, 3- methylenedioxy- (8-> 9)- 10, 12- methylenedioxy- benzoic-16-acid (2), 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline (3) and 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline-N-oxide (4). The new alkaloids were tested in human hepatoma cell line to assess their ability to modulate the expression of low-density lipoprotein receptor (LDL-R), of proprotein convertase subtilisin/kexin 9 (PCSK9) and to affect cellular cholesterol biosynthesis with the aim to evaluate their potential hypocholesterolemic effect. Results indicated that compounds 2 and 3 upregulate the LDLR, and inhibited the cholesterol biosynthesis with compound 2, which also reduced the secretion of PCSK9 by Huh7 cells. These in vitro data indicated a potential hypocholesterolemic effect of compound 2 that requires further in vivo validation.

Structural variety and pharmacological potential of naphthylisoquinoline alkaloids.

Naphthylisoquinoline alkaloids are a fascinating class of natural biaryl compounds. They show characteristic mono- and dimeric scaffolds, with chiral axes and stereogenic centers. Since the appearance of the last comprehensive overview on these secondary plant metabolites in this series in 1995, the number of discovered representatives has tremendously increased to more than 280 examples known today. Many novel-type compounds have meanwhile been discovered, among them naphthylisoquinoline-related follow-up products like e.g., the first seco-type (i.e., ring-opened) and ring-contracted analogues. As highlighted in this review, the knowledge on the broad structural chemodiversity of naphthylisoquinoline alkaloids has been decisively driven forward by extensive phytochemical studies on the metabolite pattern of Ancistrocladus abbreviatus from Coastal West Africa, which is a particularly "creative" plant. These investigations furnished a considerable number of more than 80-mostly new-natural products from this single species, with promising antiplasmodial activities and with pronounced cytotoxic effects against human leukemia, pancreatic, cervical, and breast cancer cells. Another unique feature of naphthylisoquinoline alkaloids is their unprecedented biosynthetic origin from polyketidic precursors and not, as usual for isoquinoline alkaloids, from aromatic amino acids-a striking example of biosynthetic convergence in nature. Furthermore, remarkable botanical results are presented on the natural producers of naphthylisoquinoline alkaloids, the paleotropical Dioncophyllaceae and Ancistrocladaceae lianas, including first investigations on the chemoecological role of these plant metabolites and their storage and accumulation in particular plant organs.

Navigating Amaryllidaceae Alkaloids: Bridging Gaps and Charting Biosynthetic Territories - A Comprehensive Review.

Amaryllidaceae alkaloid (AAs) biosynthesis has garnered significant attention in recent years, particularly with the commercialisation of galanthamine as a treatment for the symptoms of Alzheimer's disease. A significant amount of research work over the last 8 decades has focused on the understanding of AA biosynthesis, starting from early radiolabelling studies to recent multi-omics analysis with modern biotechnological advancements. Those studies enabled the identification of hundreds of metabolites, the characterisation of biochemical pathway, an understanding of the environmental stimuli, and of the molecular regulation of these pharmaceutically and agriculturally important metabolites. Despite the numerous works there remain significant gaps in understanding their biosynthesis in Amaryllidaceae plants. As such, further research is needed to fully elucidate the metabolic pathway and facilitate their production. This review aims to provide a comprehensive overall summary of the current state of knowledge on AAs biosynthesis, from elicitation of transcription factors expression in the cell nucleus to alkaloid transport in the apoplast, and to highlight the challenges that need to be overcome for further advancement.

Biologically active isoquinoline alkaloids covering 2019-2022.

Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research.

Variability of Isoquinoline Alkaloid Profiles and Anticholinesterase Activities with Binding-Mode Predictions of Glaucium flavum Population.

In this study, phytochemical and biological activity studies supported by docking were carried out on a species of the genus Glaucium, a repository of isoquinoline alkaloids. The GC-MS (Gas Chromatography-Mass Spectrometry) method is used to characterize the isoquinoline alkaloids of Glaucium flavum Crantz. (Papaveraceae). G. flavum was collected from seven different regions of Türkiye (Antalya, Urla-Izmir, Mordogan-Izmir, Mugla, Assos-Canakkale, Karabiga-Canakkale, Giresun) and totally 17 compounds were detected by GC-MS. Glaucine was found to be the major constituent in the sample collected from Mugla, whereas isocorydine was recorded to be the principal alkaloid in other samples. Further fractionation studies on G. flavum collected from Antalya province in Southwestern Türkiye, yielded five major alkaloids (isocorydine 1, dihydrosanguinarine 2, glaucine 3, dehydroglaucine 4, protopine 5) which were characterized by spectroscopic methods. Anticholinesterase activities of the extracts and isolated alkaloids were also tested by in vitro Ellman method. The isolated compounds were also analyzed by a molecular docking technique to determine the binding orientations in the gorge of the active site of acetylcholinesterase (AChE) and a homology model of butyrylcholinesterase (BuChE). This is the first comparative investigation of the phytochemical composition and biodiversity of Glaucium flavum species growing in Türkiye.

A rapid localization and analysis method for isoquinoline alkaloids with fluorescence in Coptis chinensis Franch. By fabricating the nano-silver sol as a substrate for surface-enhanced Raman spectroscopy.

BACKGROUND: The quality of traditional Chinese medicines (TCMs) directly impacts their clinical efficacy and drug safety, making standardization a critical component of modern TCMs. Surface-enhanced Raman spectroscopy (SERS) is an effective physical detection method with speed, sensitivity, and suitability for large sample analyses. In this study, a SERS analysis method was developed using a nano-silver sol as the matrix to address the interference of fluorescence components in TCMs and overcome the limitations of traditional detection methods. RESULTS: The higher sensitivity and efficiency of SERS was used, enabling detection of a single sample within 30 s. Coptis chinensis Franch. (CCF) was chosen as the model medicine, the nano-silver sol was used as the matrix, and CCF's fourteen main fluorescent alkaloids were tested as index components. Typical signal peaks of the main components in CCF corresponded to the bending deformation of the nitrogen-containing ring plane outer ring system, methoxy stretching vibration, and isoquinoline ring deformation vibration. Through SERS detection of different parts, the distribution content of the main active components in the cortex of CCF was found to be lower than that in the xylem and phloem. Additionally, rapid quality control analyses indicated that among the nine batches of original medicinal materials purchased from Emei and Guangxi, the main active ingredient showed a higher content. SIGNIFICANCE: A SERS-based method for the rapid localization and analysis of multiple components of TCMs was established. The findings highlight the potential of SERS as a valuable tool for the analysis and quality control of TCMs, especially for fluorescent components.

Computational investigation of four isoquinoline alkaloids against polycystic ovarian syndrome.

Hyperandrogenism, insulin resistance, and estrogen dominance are the prime defining traits of women with polycystic ovarian syndrome which disrupts hormonal, adrenal, or ovarian functions resulting in impaired folliculogenesis and excess androgen production. The purpose of this study is to identify an appropriate bioactive antagonistic ligand from isoquinoline alkaloids [palmatine (PAL), jatrorrhizine (JAT), magnoflorine (MAG) and berberine (BBR)] from stems of Tinospora cordifolia. Phytocomponents inhibit/prevent androgenic, estrogenic, and steroidogenic receptors, insulin binding, and resultant hyperandrogenism. Intending to develop new inhibitors for human androgen receptor (1E3G), insulin receptor (3EKK), estrogen receptor beta (1U3S), and human steroidogenic cytochromeP450 17A1 (6WR0), here we report the docking studies by employing a flexible ligand docking approach using AutodockVina 4.2.6. ADMET screened swissADME and toxicological predictions to identify novel and potent inhibitors against PCOS. Binding affinity was obtained using Schrodinger. Two ligands, mainly BER (-8.23) and PAL (-6.71) showed the best docking score against androgen receptors. A molecular docking study reveals that compounds BBR and PAL were found to be tight binder at the active site of IE3G. Molecular dynamics results suggest that BBR and PAL showed good binding stability of active site residues. The present study corroborates the molecular dynamics of the compound BBR and PAL, potent Inhibitors of IE3G, having therapeutic potential for PCOS. We project that this study's findings will be helpful in drug development efforts targeting PCOS. Hence isoquinoline alkaloids (BER& PAL) have potential roles against androgen receptors, and in specific PCOS, scientific evaluation has been put forth based on virtual screening.Communicated by Ramaswamy H. Sarma.

Protective effect of Macleaya cordata isoquinoline alkaloids on lipopolysaccharide-induced liver injury in broilers.

OBJECTIVE: This experiment aimed to explore the protective action of dietary supplementation with isoquinoline alkaloids (IA) from Macleaya cordata on lipopolysaccharide (LPS)-induced liver injury in broilers. METHODS: Total 216 healthy broilers were selected in a 21-d trial and assigned randomly to the following 3 treatments: control (CON) group, LPS group, and LPS+IA group. The CON and LPS groups were provided with a basal diet, whereas the LPS+IA group received the basal diet supplemented with 0.6 mg/kg Macleaya cordata IA. Broilers in LPS and LPS+IA groups were intraperitoneally injected with LPS (1 mg/kg body weight) at 17, 19, and 21 days of age, while those in CON group were injected with equivalent amount of saline solution. RESULTS: Results showed LPS injection caused systemic and liver inflammation in broilers, inhibited immune function, and ultimately lead to liver injury. By contrast, supplementation of IA ameliorated LPS-induced adverse change in serum parameters, boosted immunity in LPS+IA group. Furthermore, IA suppressed the elevation of hepatic inflammatory cytokines and caspases levels induced by LPS, as well as the expressions of genes related to the tolllike receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factorkappa B (NF-κB) pathway. CONCLUSION: Dietary inclusion of 0.6 mg/kg Macleaya cordata IA could enhance immune function of body and inhibit liver damage via inactivating TLR4/MyD88/NF-κB signaling pathway in broilers.

Identification and Analysis of NnOMT and NnNMT Gene Families in Nelumbo nucifera / 中国实验方剂学杂志

ObjectiveThe biosynthetic pathways of benzylisoquinoline alkaloids（BIAs） in Nelumbo nucifera are of great theoretical and economic value. In this paper， N. nucifera O-methyltransferase（NnOMT） and N. nucifera N-methyltransferase（NnNMT） gene families were identified and analyzed by bioinformatics in order to facilitate the biosynthetic pathway of BIAs in N. nucifera. MethodBased on the whole genome of N. nucifera， UniPort and National Center for Biotechnology Information（NCBI） databases were used to identify the NnOMT and NnNMT gene families of N. nucifera， and analyze their physicochemical properties and subcellular localization， then TBtools， MEME， MEGA 11.0， FigTree 1.4.4 and other tools were used to analyze the phylogeny， sequence characteristics， gene structure， functional annotation and cis-acting elements of NnOMT and NnNMT genes identified in the previous stage. ResultA total of 61 NnOMT and NnNMT genes were identified in this paper， the number of amino acids encoded by these genes ranged from 168 aa to 580 aa， the isoelectric point ranged from 4.76 to 9.16， and the relative molecular weight ranged from 18 699.52 Da to 64 934.53 Da， most of which showed acidic and mostly hydrophilic proteins. There were 10 conserved motifs， Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis enriched a total of 12 pathways， including metabolism， biosynthesis of phenylpropane and isoquinoline alkaloids， etc. And Visualization of Gene Ontology（GO） enrichment results showed that 61 NnOMT and NnNMT genes were annotated to 32 items， which included 16 molecular functions［such as reduced nicotinamide adenine dinucleotide（NADH） activity and exopeptidase activity］ and 16 biological processes（such as metabolic process of carbon tetrachloride， anaerobic carbon tetrachloride metabolic process and responses to exogenous biological stimuli）. There were a variety of cis-acting elements in the promoter regions of NnOMT and NnNMT genes， mainly promoter and enhancer regions element， light responsive element and methyl jasmonate responsive element. ConclusionIn this study， a comprehensive bioinformatics analysis of 61 NnOMT and NnNMT genes is carried out based on the genome data of N. nucifera， which lays a foundation for research on the gene structure and function of NnOMT and NnNMT gene families， and provides a reference for biosynthetic pathway elucidation of BIAs in N. nucifera.

Transcriptome and Metabolome Analysis of Isoquinoline Alkaloid Biosynthesis of Coptis chinensis in Different Years.

Coptis chinensis is a perennial herb of the Ranunculaceae family. The isoquinoline alkaloid is the main active component of C. chinensis, mainly exists in its rhizomes and has high clinical application potential. The in vitro synthesis of isoquinoline alkaloids is difficult because their structures are complex; hence, plants are still the main source of them. In this study, two-year and four-year rhizomes of C. chinensis were selected to investigate the effect of growth years on the accumulation of isoquinoline alkaloids. Two-year and four-year C. chinensis were selected for metabolomics detection and transcriptomic analysis. A total of 413 alkaloids were detected by metabolomics analysis, of which 92 were isoquinoline alkaloids. (S)-reticuline was a significantly different accumulated metabolite of the isoquinoline alkaloids biosynthetic pathway in C. chinensis between the two groups. The results of transcriptome analysis showed that a total of 464 differential genes were identified, 36 of which were associated with the isoquinoline alkaloid biosynthesis pathway of C. chinensis. Among them, 18 genes were correlated with the content of important isoquinoline alkaloids. Overall, this study provided a comprehensive metabolomic and transcriptomic analysis of the rapid growth stage of C. chinensis rhizome from the perspective of growth years. It brought new insights into the biosynthetic pathway of isoquinoline alkaloids and provided information for utilizing biotechnology to improve their contents in C. chinensis.

Cytotoxic activity of isoquinoline alkaloids and herbal extracts from selected plants against human cancer cell lines: harnessing the research potential in cancer drug discovery with modern scientific trends and technology.

The increasing prevalence of cancer has led to a growing interest in alternative medicine methods and treatments. This study aimed to assess the cytotoxicity of isoquinoline alkaloids and herbal extracts from selected plants against human cancer cell lines, including melanoma and squamous cell carcinoma. The investigation involved in vitro cell viability assays using various cancer cell lines and normal skin fibroblasts as control cells. Additionally, a zebrafish model was employed for in vivo evaluation of cytotoxic activity. The results indicated that the tested alkaloids and extracts exhibited promising cytotoxic effects, showing higher potency than standard chemotherapeutic drugs. In comparison, these findings support the exploration of isoquinoline alkaloids and herbal extracts as potential candidates for developing novel anti-melanoma and anti-squamous cell carcinoma drugs. The primary inclusion criterion that was taken into consideration in this study effort was the therapeutic application of the cytotoxic effects of specific plant-based pharmacological components or chemicals produced from herbal extracts that are ordinarily cytotoxic.

Morphinan and isoquinoline alkaloids from the tuberous roots of Stephania cepharantha.

A new morphinan alkaloid (6S, 9S, 13 R, 14S)-6-O-acetyl-7,8-Didehydro-4-hydroxy-3,7-dimethoxymorphinan-6-ol (1), and a new naturally occurring cularine alkaloid (S)-2, 3, 12, 12a-tetrahydro-5, 6, 9, 10-tetramethoxy-1-methyl-1H-[1]benzoxepino[2, 3, 4-ij]isoquinoline(5), along with four known alkaloids were isolated from the roots of Stephania cepharantha. The structures of these compounds were elucidated based on spectroscopic data analyses. Cytotoxic activities of the compounds against three human cancer cell lines (A549, MCF-7 and SW480) were also evaluated.

New trends in the practical use of isoquinoline alkaloids as potential drugs applicated in infectious and non-infectious diseases.

In the last years, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding permanently. Isoquinoline alkaloids have always attracted scientific interest due to either their positive or negative effects on human organism. The present review describes research on isoquinoline alkaloids isolated from different plant species. Alkaloids are one of the most important classes of plant derived compounds among these isoquinoline alkaloids possess varied biological activities such as anticancer, antineurodegenerative diseases, antidiabetic, antiinflammatory, antimicrobial, and many others. The use of plants against different disorders is entrenched in traditional medicine around the globe. Recent progress in modern therapeutics has stimulated the use of natural products worldwide for various ailments and diseases. The review provides a collection of information on the capabilities of some isoquinoline alkaloids, its potential for the treatment of various diseases and is designed to be a guide for future research on different biologically active isoquinoline alkaloids and plant species containing them. The authors are aware that they were not able to cover the whole area of the topic related to biological activity of isoquinoline alkaloids. This review is intended to suggest directions for further research and can also help other researchers in future studies.

Three new isoquinoline alkaloids from the fermentation of Aspergillus sp. 0338 and their anti-MRSA activities.

There is growing evidence that bioactive substances produced by microbial endophytes have applicability in medicine, agriculture and industry. To enrich the bioactive substances, in our search for new bioactive metabolites from fungi Aspergillus, the phytochemical reinvestigation on the Aspergillus sp. 0338 was carried out, and this led to the isolation of three new (1-3) and five known alkaloids (4-8). Their structures were elucidated by spectroscopic analysis, including extensive 1D and 2D NMR techniques, as well as comparison with literature values. Additionally, compounds 1-3 were evaluated for their anti-MRSA activities. The results revealed that compounds 1-3 exhibited good inhibitions with IZD of 15.2 ± 1.8, 14.6 ± 2.0, and 13.4 ± 2.2 mm, respectively.

[Two new isoquinoline alkaloids from Corydalis hendersonii].

Corydalis hendersonii(CH) is a Tibetan folk medicine with the functions of clearing heat, detoxifying, cooling blood, checking diarrhea, and lowering blood pressure. It is often used to treat high altitude polycythemia, vasculitis, peptic ulcer, and diarrhea. Nine compounds were separated from the ethanol extract of CH by silica gel, ODS, Sephadex LH-20 chromatography and semi-preparative HPLC. Their structures were identified as hendersine H(1),hendersine I(2), dehydrocheilanthifoline(3), protopine(4), izmirine(5), 6,7-methylenedioxy-1(2H)-isoquinolinone(6), icariside D_2(7), ethyl 4-(ß-D-glucopyranosyloxy)-3-methoxybenzoate(8), 3-hydroxy-4-methoxybenzoic acid(9), respectively, by the spectroscopic data analysis and comparison with those in the literature. Among them, compounds 1 and 2 are new isoquinoline alkaloids, and compounds 7-9 are reported the first time for Corydalis. The hypoglycemic model of H9c2 cardiomyocytes and the inflammatory model of H9c2 cardiomyocytes induced by conditional supernatant were employed to determine the activities of the above compounds. The results showed that 20 µmol·L~(-1) compound 1 had a protective effect on H9c2 cardiomyocytes and 10 µmol·L~(-1) compounds 4 and 5 inhibited H9c2 cardiomyocyte inflammation induced by conditional supernatant.

Discovery and biological evaluation of a new type of dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase from ethnomedicinal plant Dactylicapnos scandens.

The root of Dactylicapnos scandens (D.Don.) Hutch (Papaveraceae), one of the most famous ethno-medicinal plants from the Bai communities in P. R. China, is used to treat various inflammations and tumours. Bioassay-guided phytochemical research on D. scandens followed by semi-synthesis led to a series of undescribed tetrahydroisoquinoline alkaloids with dual inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). The previously undescribed dark-green alkaloid dactycapnine A exhibited the best dual inhibitor effects among the identified compounds. Structure-activity relationship analysis revealed the importance of the base skeleton with a hyperconjugation system. The performed semi-synthesis further yielded bioactive dimeric and trimeric compounds with hyperconjugated systems. Performed STD NMR experiments disclosed direct interactions between dactycapnine A and IDO1/TDO. Inhibition kinetics indicated dactycapnine A as a mixed-type dual inhibitor. These findings provided a possible explanation for the anticancer properties of the ethno-medicinal plant species D. scandens.

[Characterization and identification of alkaloids in Phellodendri Chinensis Cortex and Phellodendri Amurensis Cortex based on UHPLC-IM-Q-TOF-MS].

A strategy combining collision cross section(CCS) prediction and quantitative structure-retention relationship(QSRR) model for quinoline and isoquinoline alkaloids was established based on UHPLC-IM-Q-TOF-MS and applied to Phellodendri Chinensis Cortex and Phellodendri Amurensis Cortex. The strategy included the following three steps.(1) The molecular features were extracted by the "find features" algorithm.(2) The potential quinoline and isoquinoline alkaloids were screened by filtering the original characteristic ions extracted from Phellodendri Chinensis Cortex and Phellodendri Amurensis Cortex by the established CCS vs m/z prediction interval.(3) According to the retention time of candidate compounds predicted by QSRR model, the chemical constituents were identified in combination with the characteristic fragment ions and pyrolysis law of secondary mass spectrometry. With the strategy, a total of 80 compounds were predicted, and 15 were identified accurately. The strategy is effective for the identification of small analogs of traditional Chinese medicine.

Research Progress on Neuroprotective Effects of Isoquinoline Alkaloids.

Neuronal injury and apoptosis are important causes of the occurrence and development of many neurodegenerative diseases, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Although the detailed mechanism of some diseases is unknown, the loss of neurons in the brain is still the main pathological feature. By exerting the neuroprotective effects of drugs, it is of great significance to alleviate the symptoms and improve the prognosis of these diseases. Isoquinoline alkaloids are important active ingredients in many traditional Chinese medicines. These substances have a wide range of pharmacological effects and significant activity. Although some studies have suggested that isoquinoline alkaloids may have pharmacological activities for treating neurodegenerative diseases, there is currently a lack of a comprehensive summary regarding their mechanisms and characteristics in neuroprotection. This paper provides a comprehensive review of the active components found in isoquinoline alkaloids that have neuroprotective effects. It thoroughly explains the various mechanisms behind the neuroprotective effects of isoquinoline alkaloids and summarizes their common characteristics. This information can serve as a reference for further research on the neuroprotective effects of isoquinoline alkaloids.

In silico investigation and potential therapeutic approaches of isoquinoline alkaloids for neurodegenerative diseases: computer-aided drug design perspective.

Microtubule affinity regulating kinase (MARK4) has been proposed as a potential therapeutic target for diabetes, cancer, and neurological diseases. We used a variety of computational studies techniques to examine the binding affinity and MARK4 inhibitory potential of several isoquinoline alkaloids. MARK4 has been associated with tau protein phosphorylation and, consequently, Alzheimer's disease. The three molecules with the highest binding affinities inside the 5ES1 receptor, according to molecular docking experiments, are isoliensinine, liensinine, and methylcorypalline. Isoliensinine had the highest drug score and drug likeness, coming in at 1.17, while Liensinine and Methylcorypalline came in at 1.15 and 1.07, respectively. The thesis claims that three compounds have a better chance than the others of being identified as therapeutic leads. The bulk of the compounds under investigation didn't break any of Lipinski's five rules, especially methylcorypalline, which did and is probably orally active. The majority of the compounds under investigation, particularly Isoliensinine, Liensinine, and Methylcorypalline, show the potential to exhibit drug-like behaviour, which is strongly confirmed by ADMET characteristics estimates. The chemicals Isoliensinine, Liensinine, and Methylcorypalline, especially Methylcorypalline, form the most stable combination with the 5ES1, according to a 100 ns molecular dynamics simulation of these compounds docked inside 5ES1 complexes. Methylcorypalline has a higher binding affinity inside 5ES1, according to additional MM/GBSA experiments using MD trajectories. Overall, research supports the use of the drug development tool methylcolipalin for its ability to inhibit MARK4, which may have implications for the treatment of neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.

Determination of Some Isoquinoline Alkaloids in Extracts Obtained from Selected Plants of the Ranunculaceae, Papaveraceae and Fumarioideae Families by Liquid Chromatography and In Vitro and In Vivo Investigations of Their Cytotoxic Activity.

Alkaloids are heterocyclic bases with widespread occurrence in nature. Plants are rich and easily accessible sources of them. Most isoquinoline alkaloids have cytotoxic activity for different types of cancer, including malignant melanoma, the most aggressive type of skin cancer. The morbidity of melanoma has increased worldwide every year. For that reason, developing new candidates for anti-melanoma drugs is highly needed. The aim of this study was to investigate the alkaloid compositions of plant extracts obtained from Macleaya cordata root, stem and leaves, Pseudofumaria lutea root and herb, Lamprocapnos spectabilis root and herb, Fumaria officinalis whole plant, Thalictrum foetidum root and herb, and Meconopsis cambrica root and herb by HPLC-DAD and LC-MS/MS. For determination of cytotoxic properties, human malignant melanoma cell line A375, human Caucasian malignant melanoma cell line G-361, and human malignant melanoma cell line SK-MEL-3 were exposed in vitro to the tested plant extracts. Based on the in vitro experiments, Lamprocapnos spectabilis herb extract was selected for further, in vivo research. The toxicity of the extract obtained from Lamprocapnos spectabilis herb was tested using an animal zebrafish model in the fish embryo toxicity test (FET) for determination of the LC50 value and non-toxic doses. Determination of the influence of the investigated extract on the number of cancer cells in a living organism was performed using a zebrafish xenograft model. Determination of the contents of selected alkaloids in different plant extracts was performed using high performance liquid chromatography (HPLC) in a reverse-phase system (RP) on a Polar RP column with a mobile phase containing acetonitrile, water and ionic liquid. The presence of these alkaloids in plant extracts was confirmed by LC-MS/MS. Preliminary cytotoxic activity of all prepared plant extracts and selected alkaloid standards was examined using human skin cancer cell lines A375, G-361, and SK-MEL-3. The cytotoxicity of the investigated extract was determined in vitro by cell viability assays (MTT). For in vivo determination of investigated extract cytotoxicity, a Danio rerio larvae xenograft model was used. All investigated plant extracts in in vitro experiments exhibited high cytotoxic activity against the tested cancer cell lines. The results obtained using the Danio rerio larvae xenograft model confirmed the anticancer activity of the extract obtained from Lamprocapnos spectabilis herb. The conducted research provides a basis for future investigations of these plant extracts for potential use in the treatment of malignant melanoma.