Proaporphine Alkaloids Research Articles

A systematic review of proaporphine alkaloids and a pharmacological update

BackgroundProaporphine alkaloids are present in many plant families. They are often considered as metabolic precursors to aporphines. They generally contain a cyclohexadienone system and can rearrange to aporphines on treatment with acid. Typical proaporphines include the alkaloids pronuciferine, stepharine, crotsparine, glaziovine and many analogues with different substitution patterns. The proaporphine glaziovine has been used in human as a tranquilizer to treat anxiety and depression but otherwise proaporphines have received little attention as medicinal products. Proaporphines have been neglected compared to aporphines. PurposeThe present review provides a survey of a hundred of proaporphine alkaloids isolated from plants, divided into three groups: conventional proaporphines (including mecambrine, roemeronine and orientalinone among others), homoproaporphines with a tetracyclic or pentacyclic core (such as kreysiginone and robustamine), and various proaporphine hybrid molecules (roemeridine, magnostepharine and diverse analogues). ResultsThe structural diversity of proaporphines is presented. The properties of prototypic proaporphine alkaloids are discussed, and their mechanisms of action are underlined. The case of atypical but promising proaporphine dimers, such as distepharinamide targeting tumor infiltrating T regulatory cells, is also addressed. ConclusionThe analysis offers a survey of the proaporphine landscape with the goal to highlight the molecular diversity in the family and to encourage further researches into their mechanism of action and medicinal properties.

Chemical constituents from Cyathostemma wrayi king and their chemophenetic significance

The phytochemical studies on the bark of Cyathostemma wrayi King resulted in the identification of ten alkaloids consisting of four oxoaporphines; lysicamine (1), atherospermidine (2), thalicminine (3), liriodenine (4), five aporphines; xylopine (5), nornuciferine (6), annonaine (7), norstephalagine (8), asimilobine (9), and one propaporphine; stepharine (10). The structural characterisation of all the isolated alkaloids was confirmed through the analysis of spectroscopic data and comparison with literature data. This is the first report on the alkaloids of Cyathostemma wrayi and also the first report on the occurrence of aporphine (1–3) and proaporphine (5–10) alkaloids in the genus of Cyathostemma. In addition, the chemophenetic significance of the isolated alkaloids was summarized.

ADME profiling, molecular docking, DFT, and MEP analysis reveal cissamaline, cissamanine, and cissamdine from Cissampelos capensis L.f. as potential anti-Alzheimer's agents.

The current pharmacotherapies for Alzheimer's disease (AD) demonstrate limited efficacy and are associated with various side effects, highlighting the need for novel therapeutic agents. Natural products, particularly from medicinal plants, have emerged as a significant source of potential neuroprotective compounds. In this context, Cissampelos capensis L.f., renowned for its medicinal properties, has recently yielded three new proaporphine alkaloids; cissamaline, cissamanine, and cissamdine. Despite their promising bioactive profiles, the biological targets of these alkaloids in the context of AD have remained unexplored. This study undertakes a comprehensive in silico examination of the binding affinity and molecular interactions of these alkaloids with human protein targets implicated in AD. The drug likeness and ADME analyses indicate favorable pharmacokinetic profiles for these compounds, suggesting their potential efficacy in targeting the central nervous system. Molecular docking studies indicate that cissamaline, cissamanine, and cissamdine interact with key AD-associated proteins. These interactions are comparable to, or in some aspects slightly less potent than, those observed with established AD drugs, highlighting their potential as novel therapeutic agents for Alzheimer's disease. Crucially, Density Functional Theory (DFT) calculations offer deep insights into the electronic and energetic characteristics of these alkaloids. These calculations reveal distinct electronic properties, with differences in total energy, binding energy, HOMO-LUMO gaps, dipole moments, and electrophilicity indices. Such variations suggest unique reactivity profiles and molecular stability, pertinent to their pharmacological potential. Moreover, Molecular Electrostatic Potential (MEP) analyses provide visual representations of the electrostatic characteristics of these alkaloids. The analyses highlight areas prone to electrophilic and nucleophilic attacks, indicating their potential for specific biochemical interactions. This combination of DFT and MEP results elucidates the intricate electronic, energetic, and electrostatic properties of these compounds, underpinning their promise as AD therapeutic agents. The in silico findings of this study shed light on the promising potential of cissamaline, cissamanine, and cissamdine as agents for AD treatment. However, further in vitro and in vivo studies are necessary to validate these theoretical predictions and to understand the precise mechanisms through which these alkaloids may exert their therapeutic effects.

Phytochemical composition and antidiabetic potential of the leaf, stem, and rhizome extracts of Cissampelos capensis L.f

Diabetes mellitus has a growing global prevalence and complications resulting from type 2 diabetes have been recorded to lead to death. The endemic medicinal plant Cissampelos capensis L.f. has been identified as an important plant in the management of diabetes by local people in southern Africa. The current work was designed to evaluate the in vitro cytotoxic, antioxidant, and α-amylase – and α-glucosidase inhibition of C. capensis based on its believed antidiabetic potential. The phytochemical analysis was performed through qualitative (HPTLC), and quantitative (UV–Vis spectrophotometry and LC-MS) analysis, while the in vitro MTT cytotoxicity, ORAC – and DPPH radical scavenging assays, α-glucosidase – and α-amylase inhibition potential of leaf, stem, and rhizome methanolic – (MCCL, MCCS, and MCCR) and TTA crude extracts (TTA CCL, TTA CCS, and TTA CCR) of C. capensis were accessed. Additionally, the cytotoxicity and enzymatic potential of five previously reported bioactive proaporphine alkaloids (glaziovine, pronuciferine, cissamaline, cissamanine, and cissamdine) isolated from C. capensis were evaluated. The phytochemical analysis revealed the highest presence of alkaloids followed by flavonoids, phenols, and terpenes. MCCL (93.740 ± 11.634 %), TTA CCS (77,818 ± 2,590 %), and TTA CCR (60,375 ± 12,722 %) exhibited the highest cell viability at 125 µg/mL, respectively, better than that of the positive control, Melphalan (62.5 µM). Where the The ORAC – and DPPH radical scavenging assays generally exhibited strong antioxidant activity for the rhizome and stem methanolic extracts. The α-glucosidase inhibition was strongest for the rhizome and stem extracts and comparable to that of the control. However, α-amylase inhibition was stronger for the leaf and rhizome extracts, and only comparable to the control at 500 µg/mL. All the isolated proaporphine alkaloids exhibited concentration dependant cytotoxicity, with moderate α-amylase inhibition at 500 µg/mL while no α-glucosidase inhibition was observed. The potential antioxidants and enzymatic inhibition combined with the moderate cytotoxicity of C. capensis and its isolated bioactive proaporphine alkaloids make it a good source of a possible new type II diabetic targets.

Three new proaporphine alkaloids from Cissampelos capensis L.f. and their cytotoxic evaluation

Three new proaporphine alkaloids, cissamaline (4), cissamanine (5), and cissamdine (6), along with two known compounds (2 and 3) were isolated from total tertiary alakloidal extracts of the leaves and stems of Cissampelos capensis. The new alkaloids were elucidated through comprehensive spectroscopic analysis, including 1 D, 2 D NMR and High-resolution LCMS. The in vitro MTT cytotoxicity was evaluated on Caco-2 cell lines, where all the isolated compounds exhibited cytotoxic effects at concentrations above 250 µM.

Novel Aporphine- and Proaporphine-Clerodane Hybrids Identified from the Barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula with Strong Anti-DENV2 Activity.

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C–C or N–C covalent linkage. Here, we report four structurally attractive diterpene–alkaloid conjugates polyalongarins A–D (1–4), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of 1. Compounds 1–4 were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC50 (2.8–6.4 μM) and CC50 values (50.4–200 μM). The inhibitory mechanism of 1–4 on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of 1–4 and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane–aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors.

Concise Synthesis of the ABC-Ring System of the Azafluoranthene, Tropoisoquinoline and Proaporphine Alkaloids: An Olefin Hydroacylation/Pomeranz–Fritsch Cyclization Approach

A straightforward approach toward a decorated cyclopenta[ij]isoquinoline embodying the ABC-ring system characteristic of the azafluoranthene (triclisine), tropoisoquinoline (pareitropone) and proaporphine (prodensiflorin B) alkaloids, is reported. The synthetic ­sequence entailed a novel 40% KF/Al2O3-mediated hydroacylation of a 2-allyl-benzaldehyde derivative, obtained in two steps from isovanillin, through O-allylation and Claisen rearrangement to assemble the AC-ring system. This was followed by an O-methylation and a reductive ­amination of the resulting indanone with aminoacetal. A modified Pomeranz–Fritsch cyclization was next implemented to install ring B, through sulfonamidation, followed by acid-promoted cyclization and ­final desulfonylation in situ.

Alkaloids from the stems and rhizomes of Sinomenium acutum from the Qinling Mountains, China

Thirteen undescribed alkaloids (sinotumines A−M), including five oxoisoaporphine, a benzo[h]quinoline, an aporphine, two protoberberine, two hasubanane, and two proaporphine alkaloids, and 50 known analogues were isolated from the 95% aqueous EtOH extract of the stems and rhizomes of Sinomenium acutum. The structures and absolute configurations of the isolates were elucidated on the basis of comprehensive analysis of 1D and 2D NMR, HRMS, single-crystal X-ray diffraction, and comparison of the experimental and calculated electronic circular dichroism (ECD) data. Sinotumine F, a rare benzo[h]quinoline alkaloid, was speculated as an oxidation product of the oxoisoaporphine alkaloid, and its putative biosynthetic pathway is proposed. Sinotumines L and M are the first samples of proaporphine-based heterodimers coupled with 1-heptanone and coniferol alcohol moiety, respectively. The T-cell suppression and NO inhibition effects of the isolates were evaluated.

Alkaloids from Cryptocarya densiflora Blume (Lauraceae) and their cholinesterase inhibitory activity

(−)-Desmethylsecoantofine N-oxide (1), a new seco-phenanthroindolizidine alkaloid along with prodensiflorins A and B (2-3), two new proaporphine alkaloids, were isolated from the leaves of Cryptocarya densiflora Blume. Their structures were established on the basis of 1D and 2D NMR techniques and LCMS-IT-TOF analysis. (+)-N-methyllaurotetanine (4), (+)-laurotetanine (5), (+)-nornantenine (6), crychine (7), (−)-isocaryachine (8), (+)-reticuline (9), (−)-desmethylsecoantofine (10), (+)-oridine (11), dicentrinone (12) and (−)-antofine (13) were also isolated with compounds 4, 7–9 and 12–13 being characterized for the first time in this plant. Compounds 1-3 were moderate to weak AChE and BChE inhibitors while compound 10 was a DPPH free radical scavenger.

Aporphine alkaloids from the leaves of Phoebe grandis (Nees) Mer. (Lauraceae) and their cytotoxic and antibacterial activities.

The oxoaporphine alkaloid lysicamine (1), and three proaporphine alkaloids, litsericinone (2), 8,9,11,12-tetrahydromecambrine (3) and hexahydromecambrine A (4) were isolated from the leaves of Phoebe grandis (Nees) Merr. (Lauraceae). Compounds 2 and 3 were first time isolated as new naturally occurring compounds from plants. The NMR data for the compounds 2–4 have never been reported so far. Compounds 1 and 2 showed significant cytotoxic activity against a MCF7 (human estrogen receptor (ER+) positive breast cancer) cell line with IC50 values of 26 and 60 µg/mL, respectively. Furthermore, in vitro cytotoxic activity against HepG2 (human liver cancer) cell line was evaluated for compounds 1–4 with IC50 values of 27, 14, 81 and 20 µg/mL, respectively. Lysicamine (1) displayed strong antibacterial activity against Bacillus subtilis (B145), Staphylococcus aureus (S1434) and Staphylococus epidermidis (a clinically isolated strain) with inhibition zones of 15.50 ± 0.57, 13.33 ± 0.57 and 12.00 ± 0.00 mm, respectively. However, none of the tested pathogenic bacteria were susceptible towards compounds 2 and 3.

Cytotoxic and Anti-HIV Phenanthroindolizidine Alkaloids from Cryptocarya chinensis†

Bioassay-guided fractionation of the cytotoxic ethanol extract of Cryptocarya chinensis has led to the isolation of 11 compounds, including two phenanthroindolizidine alkaloids [(-)-antofine (1) and dehydroantofine (2)], five pavine alkaloids (3-7), and four proaporphine alkaloids (8-11). The structures of the isolated compounds were determined by means of NMR spectroscopic methods, and supported by HRMS and optical rotation data. Compounds 1 and 2 showed cytotoxic activity against four cancer cell lines, L1210, P388, A549, and HCT-8, with 1 being the most potent against A549 and HCT-8 with EC50 values of 0.002 and 0.001 microg/mL, respectively. In addition, 2 is first reported to exhibit significant anti-HIV activity.

Saldedines A and B, Dibromo Proaporphine Alkaloids from a Madagascan Tunicate

Two new dibromo proaporphine alkaloids, designated saldedines A (1) and B (2), were isolated from an unidentified tunicate collected at Salary Bay, Madagascar. Saldedines A and B are the first marine proaporphine alkaloids. Their structures were elucidated by extensive spectroscopic means, and the structure of 1 was confirmed by single-crystal X-ray diffraction analysis. Both saldedines A and B were tested for toxicity to brine shrimp and showed moderate activity.

New proaporphines from the bark of Phoebe scortechinii

The phytochemical study of the bark of Malaysian Phoebe scortechinii (Lauraceae) has resulted in the isolation and identification of two new proaporphine alkaloids; (+)-scortechiniine A (1) and (+)-scortechiniine B (2) together with two known proaporphines; (−)-hexahydromecambrine A (3), (−)-norhexahydromecambrine A (4), and one aporphine; norboldine (5). Structural elucidations of these alkaloids were performed using spectroscopic methods especially 1D and 2D 1H and 13C NMR.

Novel and Efficient Synthetic Path to Proaporphine Alkaloids: Total Synthesis of (.+‐.)‐Stepharine (Ia) and (.+‐.)‐Pronuciferine (Ib).

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Novel and Efficient Synthetic Path to Proaporphine Alkaloids: Total Synthesis of (±)-Stepharine and (±)-Pronuciferine

[reaction: see text] A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where an unprecedented carbon-carbon bond forming reaction between the para-position of a phenol group and an enamide-carbon took place smoothly to give the desired spiro-cyclohexadienone.

Alkaloids of the wood of Cryptocarya chinensis.

Four new pavine alkaloids, (+)-eschscholtzidine-N-oxide (1), (-)-12-hydroxycrychine (2), (-)-12-hydroxy-O-methylcaryachine (3), and (-)-N-demethylcrychine (4), and four new proaporphine alkaloids, isocryprochine (5), prooxocryptochine (6), isoamuronine (7), and (+)-8,9-dihydrostepharine (8), together with nine known compounds were isolated from an ethanol extract of the wood of Cryptocarya chinensis. Their structures were elucidated by spectral analysis (NMR and MS), and the structures of 2 and 5 were confirmed by X-ray crystallography.

Anti-herpes simplex virus activity of alkaloids isolated from Stephania cepharantha.

By screening water and MeOH extracts of 30 Chinese medicinal plants for their anti-herpes simplex virus (HSV)-1 activity, a MeOH extract of the root tubers of Stephania cepharantha HAYATA showed the most potent activity on the plaque reduction assay with an IC50 value of 18.0 microg/ml. Of 49 alkaloids isolated from the MeOH extract, 17 alkaloids were found to be active against HSV-1, including 13 bisbenzylisoquinoline, 1 protoberberine, 2 morphinane and 1 proaporphine alkaloids, while benzylisoquinoline and hasubanane alkaloids were inactive. Although N-methylcrotsparine was active against HSV-1, as well as HSV-1 thymidine kinase deficient (acyclovir resistant type, HSV-1 TK-) and HSV-2 (IC50 values of 8.3, 7.7 and 6.7 microg/ml, respectively), it was cytotoxic. FK-3000 was found to be the most active against HSV-1, HSV-1 TK- and HSV-2 (IC50 values of 7.8, 9.9 and 8.7 microg/ml) with in vitro therapeutic indices of 90, 71 and 81, respectively. FK-3000 was found to be a promising candidate as an anti-HSV agent against HSV-1, acyclovir (ACV) resistant-type HSV-1 and HSV-2.

Development and applications of new reactions for construction of basic structures of natural products

This review deals with the development of efficient methods to construct the basic structure of natural products and the versatile methods to control the stereochemistry, and these methods were applied to the synthesis of natural compounds. The photochemical spirodienone formation reaction was applied to the synthesis of proaporphine alkaloids. The alternative spirodienone formation reactions by the metal-catalyzed degradation reaction of phenolic alpha-diazoketones were applied to many natural spirocyclic compounds, such as chamigrane type sesquiterpenes, spirovetivane type phytoalexins, marine natural products, and so on. Lewis acid mediated spirocyclization reaction of cyclohexene bis-acetal derivative was developed, and this reaction was applied to the synthesis of aphidicolane and stemodane diterpenes. The regioselective cleavage reaction of the cyclopropane ring of tricyclooctanone derivatives was used for the syntheses of diquinane and triquinane compounds. A chiral pool synthesis of several aromadendrane sesquiterpenes was achieved via common tricyclic enone intermediates. The synthesis of macrocarpals, coupling products of aromadendrane skeleton and isopentylphloroglucinol dialdehyde, was also accomplished for the first time using an arene Cr(CO)3 complex as a chiral benzyl cation equivalent. The Fe(diene)(CO)3 complexes were used for the highly stereoselective asymmetric synthesis of several natural products, such as insect pheromones and alkaloid, as a versatile mobile chiral auxiliary.

ChemInform Abstract: Synthesis of Proaporphine Alkaloids.

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Synthesis of Proaporphine Alkaloids

Synthesis of Proaporphine Alkaloids