Aporphine Alkaloids Research Articles

Advances Towards the Synthesis of Aporphine Alkaloids: C-Ring Formation via Approaches Based on One- and Two-Bond Disconnections.

Aporphine compounds constitute a class of substances with important pharmacological properties, including anticancer, antiviral, anti-HIV, anti-inflammatory, and leishmanicidal activities. Consequently, several strategies to obtain the aporphine core have been reported. Herein this review, we provide an overview of two relevant approaches used to construct the C-ring in the synthetic routes developed. The first approach, which is based on a one-bond disconnection, allows C-ring formation using a 1-benzyl-1,2,3,4-tetrahydroisoquinoline intermediate (mainly) employing cyclization reactions catalyzed by metals or promoted by light. The second approach, which is derived from a two-bond disconnection, leads to C-ring formation via a sequence of reactions starting with [4+2] cycloadditions. Through these approaches, aporphinoids with a diverse range of substitution patterns and biological activities can be synthesized.

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome.

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.

Two New Aporphine Alkaloids from Amoora cucullata and their Antibacterial Activity

Two New Aporphine Alkaloids from Amoora cucullata and their Antibacterial Activity

Alkaloid and acetogenin-rich fraction from Annona crassiflora fruit peel inhibits proliferation and migration of human liver cancer HepG2 cells.

Plant species from Annonaceae are commonly used in traditional medicine to treat various cancer types. This study aimed to investigate the antiproliferative potential of an alkaloid and acetogenin-rich fraction from the fruit peel of Annona crassiflora in HepG2 cells. A liquid-liquid fractionation was carried out on the ethanol extract of A. crassiflora fruit peel in order to obtain an alkaloid and acetogenin-rich fraction (AF-Ac). Cytotoxicity, proliferation and migration were evaluated in the HepG2 cells, as well as the proliferating cell nuclear antigen (PCNA), vinculin and epidermal growth factor receptor (EGFR) expression. In addition, intracellular Ca2+ was determined using Fluo4-AM and fluorescence microscopy. First, 9 aporphine alkaloids and 4 acetogenins that had not yet been identified in the fruit peel of A. crassiflora were found in AF-Ac. The treatment with 50 μg/mL AF-Ac reduced HepG2 cell viability, proliferation and migration (p < 0.001), which is in accordance with the reduced expression of PCNA and EGFR levels (p < 0.05). Furthermore, AF-Ac increased intracellular Ca2+ in the HepG2 cells, mobilizing intracellular calcium stores, which might be involved in the anti-migration and anti-proliferation capacities of AF-Ac. Our results support the growth-inhibitory potential of AF-Ac on HepG2 cells and suggest that this effect is triggered, at least in part, by PCNA and EGFR modulation and mobilization of intracellular Ca2+. This study showed biological activities not yet described for A. crassiflora fruit peel, which provide new possibilities for further in vivo studies to assess the antitumoral potential of A. crassiflora, especially its fruit peel.

Chemical constituents from the leaves and branches of Annona coriacea Mart. (Annonaceae)

The phytochemical investigation of the leaves and branches of Annona coriacea Mart. (Annonaceae) led to the isolation and characterization of eight compounds: five isoquinoline-derived alkaloids, including pukateine (1), liriodenine (4), anonaine (5), obovanine (6), and norisocorydine (7); one terpene lactone known as loliolide (3); one benzoic acid derivative, 2-methoxybenzoic acid (2), and 3,4,5-trimethoxyphenol (8). All compounds, except liriodenine, are being described for the first time in the species A. coriacea, and their chemophenetics relationships were discussed. The structures were elucidated by extensive analyses of 1D and 2D NMR (COSY, HSQC, and HMBC) spectroscopy in combination with MS, and the data were compared with literature values. The NMR dataset of pukateine and obovanine was reviewed. Our results showed that A. coriacea is a typical species of the Annonaceae family and an important source of aporphine alkaloids with chemophenetic relationships with Xylopia, Duguetia, Guatteria, Artabotrys, and Goniothalamus genera.

AUTOTOXIC EFFECT OF Anagyris foetida L. ALKALOIDS CONTENT

The present study aimed to evaluate the autotoxic effect of Anagyrus foetida root, flower, and leaves alkaloids on the seed germination and growth of the same species. The pot experiment was conducted for three concentrations i.e. 4, 8, and 12% of aqueous extracts of root, flower, and leaves. Further, the seed and leaves were evaluated for their alkaloids content i.e. cytisine, aporphine, and anagyrine by high-performance liquid chromatography. The results of the study suggested that seed treated by 4% root extract showed a decrease in aporphine, cytisine, and anagyrine. While the seed treated with the flower and leaves extract (12%) showed a lower concentration of all three alkaloids as compared to untreated control. While a mixture of all three parts extracts at 4% concentration showed a minimum concentration of aporphine, cytisine, and anagyrine alkaloids in the treated seeds. Anagyrus foetida roots effectively secret allelopathic compounds which inhibit A. foetida plant germination and growth. The allelopathy effect of plants can be studied in the integrated management of poisonous plants. Results of the study suggested that the farmers should not repeat the A. foetida plantation continue two successive years.

Microbial transformation of some simple isoquinoline and benzylisoquinoline alkaloids and in vitro studies of their metabolites

Simple isoquinoline alkaloids (heliamine, dehydroheliamine), a phthalide isoquinoline alkaloid noscapine, and an aporphine alkaloid boldine are biosynthetically derived from an amino acid tyrosine. These substrates and a simple synthetic isoquinoline alkaloid (2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline) contain an isoquinoline nucleus. The biotransformation of these substrates via reduction, oxidation, hydroxylation, and N-oxidation reactions with different microorganism produced nine metabolites, namely: N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl) acetamide (Metabolite 1), heliamine N-oxide (Metabolite 2), 6,7-dimethoxyisoquinoline (Metabolite 3), 3,4-dihydro-6,7-dimethoxy isoquinolin-1-one (Metabolite 4), heliamine (Metabolite 5), dehydroheliamine N-oxide (Metabolite 6), cotarnine (Metabolite 7), 5-hydroxy cotarnine (Metabolite 8), and boldine N-oxide (Metabolite 9). Primarily, the metabolites are structurally elucidated by one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, and high-resolution electrospray ionization mass spectrometry (HR-ESIMS). Furthermore, the substrates and their isolated metabolites are evaluated in vitro for their anti-inflammatory, antimicrobial, cytotoxicity, and anticancer activities. The in vitro studies reveal that some of the isolated compounds are potential as anti-inflammatory, antitumor, and antimicrobial leads.

ANTIOXIDANT PROPERTIES AND EFFECTS OF APORPHINE ALKALOIDS AND THEIR PHENANTHRENE SECO-ISOMERS ON ACETYLCHOLINESTERASE ACTIVITY

For the first time, model’s phenanthrene seco-alkaloids (seco-glaucine and seco-boldine) obtained in the medium of subcritical water SBW) from plant aporphine alkaloids were studied as antioxidants and inhibitors of acetylcholinesterase (AChE). Antioxidant activity (in vitro) of model’s aporphine and phenanthrene alkaloids: boldine, seco-boldine, glaucine and seco-glaucine, (BD, s-BD, GL and s-GL) was studied in the reaction with a stable free radical DPPH (1,1- diphenyl-2-picrylhydrazyl). In vivo, antioxidant activity was determined in a bioluminescent test system using genetically modified E. coli strains. In experiments in vitro (DPPH-test) and in vivo (biotest) phenanthrene alkaloids s-GL and s-BD demonstrate the higher antioxidant activity than their aporphine precursors GL and BD. For the study (in vitro) of the anticholinesterase activity of alkaloids and their phenanthrene seco-isomers used the “Ellman’s method” with minor modifications. The data on the inhibitory activity of the AChE enzyme with aporphine and phenanthrene alkaloids, expressed as IC50 values obtained from dose-response curves, demonstrate that the inhibitory activity for seco-boldine (IC50 = 0.21 mM) and seco-glaucine (IC50 = 0.04 mM ) is higher than for the initial aporphine alkaloids boldine (IC50 = 0.29 mM) and glaucine (IC50 = 0.44 mM), respectively. Thus, it has been shown that phenanthrene alkaloids obtained in SBW exhibit higher antioxidant activity and better inhibiting AChE-activity than their aporphine precursors.

Alkaloids from the Leaves of Annona crassiflora and Their Cytotoxic Activity

Aporphines are a class of alkaloids mostly reported in Magnoliids. The genus Annona, Annonaceae, presents great structural diversity of these compounds. Chemical investigation of leaves from Annona crassiflora Mart. resulted in the identification of an undescribed aporphine alkaloid, which was named as crassiflorine, in addition to six known analogues: anonaine, annoretine, xylopine, tetrahydropalmatrubine, litseglutine B, and stephalagine. The structure of crassiflorine was established through 1D and 2D NMR data in combination with HREIMS and IR analyses. The cytotoxic activity for all tested compounds was marginal (IC50 > 30 μM) against breast carcinoma (MCF-7) and colorectal carcinoma (HCT-116) cell lines.

Antioxidant and Antimicrobial Screening of Isolated Alkaloids from &lt;i&gt;Tinospora crispa&lt;/i&gt;

The antioxidant capacity by DPPH radical scavenging and antimicrobial activity by disk diffusion and broth microdilution method of nine isolated alkaloids from T. crispa were evaluated. All isolated alkaloids had been divided into three groups which were aporphine alkaloids, N-formylannonaine (1), N-formylnornuciferine (2), magnoflorine (9), oxoaporphine alkaloids, lysicamine (3) and liriodenine (4); and protoberberine alkaloids, columbamine(6), dihydrodiscretamine (7) and 4,13-dihydroxy-2,8,9-trimethoxydibenzo [a,g]quinolizinium (8). Protoberberine alkaloids showed (IC50 &gt; 500-800 μg/mL) radical scavenging activity while oxaporphine alkaloids inhibited the growth of the Gram-positive bacteria, Staphylococcus aureus (+) and Enterococcus faecalis (+).The antioxidant and antimicrobial properties of different compounds support documented traditional use of T. crispa in wound healing and treatment of rheumatic, diarrhoea, ulcers, itches and wounds. Results of the present biological activity investigation further points to the potential of this plant species as a good source of natural antioxidant and preservative in food industry.

Nuciferine Inhibited the Differentiation and Lipid Accumulation of 3T3-L1 Preadipocytes by Regulating the Expression of Lipogenic Genes and Adipokines.

Purposes: Nuciferine, a main aporphine alkaloid component found in lotus leaf (Nelumbo nucifera), has been demonstrated to possess the property of reducing fat mass and alleviating dyslipidemia in vivo. The purpose of this study is to explore the effects of nuciferine on the proliferation and differentiation of 3T3-L1 cells and further investigate the possible underlying molecular mechanisms. Methods: 3T3-L1 preadipocytes were treated with 0∼20 μM nuciferine for 24∼120 h, the cell viability was assessed using CCK8. 3T3-L1 preadipocytes and human primary preadipocytes were then induced differentiation and the effects of nuciferine on the lipid metabolism in differentiating and fully differentiated adipocytes were observed by the methods of intracellular triglyceride (TG) assay, Oil Red O staining, RT-qPCR and western blot. Transient transfection and dual luciferase reporter gene methods were used to assess the effects of nuciferine on FAS promoter activities. Results: Nuciferine inhibited the proliferation of 3T3-L1 preadipocytes in a dose- and time-dependent manner. 20 μM nuciferine significantly attenuated lipid accumulation and reduced intracellular TG contents by 47.2, 59.9 and 55.4% on the third, sixth and ninth day of preadipocytes differentiation, respectively (all p < 0.05). Moreover, the mRNA levels of PPARγ, C/EBPα, C/EBPβ, FAS, ACC, HSL and ATGL were notably decreased by 39.2∼92.5% in differentiating preadipocytes when treated with 5∼20 μM nuciferine (all p < 0.05). In fully differentiated adipocytes treated with 20 μM nuciferine for 48 h, the mRNA levels of FAS, ACC and SREBP1 were remarkably downregulated by 22.6∼45.2% compared with the controls (0 μM) (all p < 0.05), whereas the expression of adipokines FGF21 and ZAG were notably promoted by nuciferine. Similarly, in fully differentiated human primary adipocytes, the mRNA levels of FAS, ACC, SREBP1 were decreased and the expression of FGF21 and ZAG were elevated after treated with nuciferine (all p < 0.05). Further mechanism studies showed that 2.5∼20 μM nuciferine significantly decreased FAS promoter activities in 3T3-L1 preadipocytes. Conclusion: Nuciferine inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. The inhibitory effects of nuciferine on adipogenesis might be due to the downregulation of PPARγ, C/EBPα and C/EBPβ, which led to the reduction of intracellular lipid accumulation in 3T3-L1 cells and by downregulating the expression of critical lipogenic enzymes, especially of FAS, which was achieved by inhibiting the FAS promoter activities. Besides, nuciferine promoted the expression of adipokines in fully differentiated adipocytes.

New compounds from the stems of Fissistigma oldhamii var. longistipitatum and their cytotoxic activities

Two new aporphine alkaloids, (R)-1,2-methylenedioxy-3,9-dimethoxy-11-hydroxy-N- carbamoyl-noraporphine (1) and 3,10,11-trimethoxy-1,2-methylenedioxy-7-oxoaporphine(2), and one new dihydrochalcone, 4′,5′-dimethoxy-2′-hydroxy-3′,6′-quinodihydrochalcone (3), along with five known alkaloids were isolated from the ethanol extracts of the stems of Fissistigma oldhamii var. longistipitatum. The compounds were obtained by various classical column chromatographic methods, and the structure elucidation was completed primarily on the basis of spectroscopic analysis, such as UV, NMR and HR-ESI-MS. The isolated compounds were subjected to evaluate cytotoxic activities in vitro, compound 1 had activity against HL-60 and HELA (IC50 value of 8.4 μM and 5.2 μM, respectively), compound 2 against MCF-7 (IC50 value of 3.7 μM), compound 3 against HEPG2 (IC50 value of 10.8 μM), respectively.

Oxocrebanine: A Novel Dual Topoisomerase inhibitor, Suppressed the Proliferation of Breast Cancer Cells MCF-7 by Inducing DNA Damage and Mitotic Arrest

BackgroundDNA topoisomerase (Topo) inhibition plays key role in breast cancer treatment. Stephania hainanensis H. S. Lo et Y. Tsoong (S. hainanensis), a Li nationality plant that has abundant aporphine alkaloids, can inhibit Topo. PurposeTo identify a dual Topo inhibitor, a deep and systematic study of active aporphine alkaloids in S. hainanensis and their mechanisms of inhibiting breast cancer proliferation and Topo activity are essential. Study designThis study aimed to assess the anti-breast cancer and Topo inhibitory activities of oxocrebanine and explore the underlying mechanisms. MethodsThe growth inhibitory activities of 12 compounds in S. hainanensis were screened by MTT assay in MCF-7, SGC-7901, HepG-2 cells, and compared with the effects on human normal mammary epithelial MCF-10A cells as non cancer control cells. The Topo inhibitory activity was assessed by DNA relaxation and unwinding assays, kDNA decatenation assay and western blot. Cell cycle and autophagy analyses were carried out with flow cytometry and staining. Acridine orange staining and α-tubulin morphology were observed by fluorescence microscopy. Western blot was used to examine microtubule assembly dynamics and the expression levels of key proteins associated with DNA damage, autophagy and mitotic arrest. ResultsOxocrebanine was the anti-breast cancer active alkaloid in S. hainanensis. It exhibited the best inhibitory effect on MCF-7 cells with an IC50 of 16.66 μmol/l, and had only weak effect on the proliferation of MCF-10A cells. Oxocrebanine inhibited Topo I and II α in a cell-free system and in MCF-7 cells. The DNA unwinding assay suggested that oxocrebanine intercalated with DNA as a catalytic inhibitor. Oxocrebanine regulated the levels of Topo I and IIα and DNA damage-related proteins. Oxocrebanine led to the mitotic arrest, and these effects occurred through both p53-dependent and p53-independent pathways. Oxocrebanine induced autophagy, abnormal α-tubulin morphology and stimulated enhanced microtubule dynamics. ConclusionOxocrebanine was the anti-breast cancer active aporphine alkaloid in S. hainanensis. Oxocrebanine was a Topo I/IIα dual inhibitor, catalytic inhibitor and DNA intercalator. Oxocrebanine caused DNA damage, autophagy, and mitotic arrest in MCF-7 cells. Oxocrebanine also disrupted tubulin polymerization. Accordingly, oxocrebanine held a great potential for development as a novel dual Topo inhibitor for effective breast cancer treatment.

Preparation, Characterization and In Vitro Antioxidant Potential of Boldine-phospholipid Complex

Background: Boldine, is an aporphine alkaloid that possesses potent antioxidant activity. Despite having enormous potential, the clinical application of boldine was restricted because of its poor bioavailability attributed to its poor aqueous solubility and rapid clearance from the body. The drug phospholipid complexation techniques were frequently employed to overcome the limitation of low bioavailability of phytoconstituents/herbal extract. Objective: The boldine phospholipid complex (BOL-PC) formulation was developed for enhancing antioxidant potential of boldine by preparing its phospholipid complex. Methods: Boldine loaded phospholipid (BOL-PC) complex was prepared by refluxing followed by solvent evaporation method and subjected to various physicochemical and spectral analysis. Further, the in-vitro antioxidant activity was evaluated by DPPH free radical scavenging method. Results: The formation of the complex was confirmed by 1H NMR and thermal analysis. SEM and PXRD revealed partial amorphization of drug in complex formed. The BOL-PC dissolution rate and solubility was significantly improved compared to the parent compound. The maximum % yield and % EE was found to be 95.92± 0.01732 and 95.89±0.3502 respectively in the optimized formulation (F3) which exhibited concentration-dependent antioxidant property. Conclusion: It was concluded from the study that the phospholipid complexation of boldine has better antioxidant potential and improved the solubility, dissolution profile which may facilitate its oral absorption and enhances its chances for clinical application.

Chemical composition of Xylopia nitida: Diterpenes and alkaloids

From the roots of Xylopia nitida, were obtained a new natural diterpene, the ent-kaur-16-en-18,19-diol and a new aporphine alkaloid, the 5,6,6a,7-tetrahydro-1-methoxy-(6aS)-4H-benzo[de][1,3]benzodioxolo [5,6-g]quinoline. Some known compounds were also isolated, ent-trachylobane, ent-trachyloban-18,19-diol, ent-trachyloban-18-oic acid, ent-trachyloban-19-oic acid, (−)-xylopine, 1-O-ethyl-β-D-glucopyranose and a mixture of β-sitosterol and stigmasterol. This is the first phytochemical study about X. nitida. In this paper chemotaxonomic significance of these compounds is discussed.

Stephapierrines A-H, new tetrahydroprotoberberine and aporphine alkaloids from the tubers of Stephania pierrei Diels and their anti-cholinesterase activities.

Eight new alkaloids, which are four new tetrahydroprotoberberine alkaloids, stephapierrines A–D (1–4), and four new aporphine alkaloids, stephapierrines E–H (5–8), together with three new naturally occurring alkaloids (9–11) and thirty-four known alkaloids (12–45) were isolated from the tubers of Stephania pierrei Diels. The structures of the new compounds were elucidated by spectroscopic analysis and physical properties. The structures of the known compounds were characterized by comparison of their spectroscopic data with those previously reported. Compound 42 exhibited the strongest acetylcholinesterase (AChE) inhibitory activity, which was more active than galanthamine, the reference drug. Compound 23 showed the highest butyrylcholinesterase (BuChE) inhibitory activity, which was also more active than galanthamine. Molecular docking studies are in good agreement with the experimental results.

Study on the pharmacokinetics, tissue distribution and excretion of laurolitsine from Litsea glutinosa in Sprague-Dawley rats

Context Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice. Objective To investigate the pharmacokinetics, tissue distribution and excretion of laurolitsine. Materials and methods A LC-MS/MS method was established and validated to determine laurolitsine concentrations in the biological matrix of rats (plasma, tissue homogenate, urine and faeces). 10 Sprague-Dawley (SD) rats were used for plasma exposure study: 5 rats were injected with 2.0 mg/kg of laurolitsine via the tail vein, and the other 5 rats were administered laurolitsine (10.0 mg/kg) by gavage. 25 SD rats used for tissue distribution study and 5 SD rats for urine and faeces excretion study: rats administered laurolitsine (10.0 mg/kg) by gavage. After administered, serial blood, tissue, urine and faeces were collected. Analytical quantification was performed by a previous LC-MS/MS method. The pharmacokinetics, bioavailability, tissue distribution and excretion of laurolitsine were described. Results The pharmacokinetic parameters of oral and intravenous administration with Tmax were 0.47 and 0.083 h, t1/2 were 3.73 and 1.67 h, respectively. Oral bioavailability was as low as 18.17%. Laurolitsine was found at a high concentration in the gastrointestinal tract, liver, lungs and kidneys (26 015.33, 905.12, 442.32 and 214.99 ng/g at 0.5 h, respectively) and low excretion to parent laurolitsine in urine and faeces (0.03 and 1.20% in 36 h, respectively). Conclusions This study established a simple, rapid and accurate LC-MS/MS method to determine laurolitsine in different rat samples and successful application in a pharmacokinetic study.

Isocorydine inhibits the proliferation of human endometrial carcinoma HEC-1B cells by downregulating the Ras/MEK/ERK signaling pathway

Objective: Isocorydine (ICD), an aporphine alkaloid, plays a role in anticancer activity that is still being evaluated. However, the exact function and mechanism of ICD in endometrial carcinoma is largely unknown. Methods: MTT, flow cytometry, western blot, immunofluorescence, RT-PCR and ELISA were used in this research. Results: In our study we showed that ICD inhibited endometrial carcinoma HEC-1B cell proliferation at certain times and concentrations. Simultaneously, ICD induced HEC-1B cells apoptosis. Further investigation indicated that ICD reduced the phosphorylation protein levels of c-Raf (rapidly accelerated fibrosarcoma), MEK1/2 (MAPK/Erk kinase) and ERK1/2 (extracellular regulated protein kinase). Moreover, a cell immunofluorescence assay confirmed that ICD reduced intracellular expression of Ras and then promoted FOXO3 (forkhead box O3) nuclear localization to furtherly increase the mRNA level of Bim and p27Kip1. Additionally, an enzyme-linked immunosorbent assay (ELISA) revealed that ICD inhibited the production of EGF (epidermal growth factor) and PDGF (Platelet-Derived Growth Factor), which indicated that ICD indirectly inhibited the activation of the Ras/MEK/ERK signaling pathway at the ligand level. Conclusion: Taken together, these data suggest for the first time that ICD inhibits cell proliferation and induces cell apoptosis in endometrial carcinoma through suppressing Ras/MEK/ERK signaling, which may provide a theoretical foundation to the application of ICD for the treatment of human endometrial carcinoma.

Palladium-Catalyzed C8 Alkylation of 1-Naphthylamides and Its Application to the Synthesis of the Core Sturctures of Aporphine and Aristolactam Alkaloids

Palladium-Catalyzed C8 Alkylation of 1-Naphthylamides and Its Application to the Synthesis of the Core Sturctures of Aporphine and Aristolactam Alkaloids

Experimental and theoretical study on spectral features, reactivity, solvation, topoisomerase I inhibition and in vitro cytotoxicity in human HepG2 cells of guadiscine and guadiscidine aporphine alkaloids

In this study, guadiscine (G1) and guadiscidine (G2), 7,7-dimethylaporphine alkaloids from Guatteria friesiana, have they geometric paramaters, vibrational behavior and quantum chemical properties (HOMO-LUMO, MEP, ALIE and Fukui indices) analyzed through a theoretical view, by density functional theory (DFT), using the Becker's three-parameter hybrid exchange functional combined with the Lee–Yang–Parr correlation functional (B3LYP) and 6–311G(2d,p) and 6–311G++(2df,3p) basis sets. The obtained geometry data were compared with x-ray data for (−)-N-acetyl-anonaine, showing close values. Vibrational analysis, together with potential energy distribution (PED) calculations, revealed several characteristic vibrations that characterize the 7,7 dimethylaporphine skeleton, besides enabling the observation of intermolecular H-bonds through dimers formation. Molecular dynamic simulations were carried out, allowing to evaluate the solvation free energies of G1 and G2 in water, methanol and ethanol, as well as H-bonds formation between G1 and G2 and the tested solvents. The antineoplastic potential of the title molecules was evaluated via molecular docking calculations with topoisomerase I complexed with DNA. Guadiscine and guadiscidine showed, respectively, binding free energies of -8.0 and -8.5 kcal/mol, while topotecan, a DNA topoisomerase I inhibitor, showed a binding free energy value of -12 kcal/mol, indicating that the studied molecules are good topoisomerase I inhibitors. In vitro cytotoxicity assay with HepG2 cell line were performed, revealing significant antitumor potential for G2.