Alkaloid Natural Products Research Articles

Polysubstituted Pyridines from 1,4-Oxazinone Precursors.

This study describes a general method for the preparation of 1,4-oxazin-2-one intermediates from acetylene dicarboxylate and β-amino alcohol precursors. Oxazinones prepared in this manner were employed in a tandem cycloaddition/cycloreversion reaction sequence with a model alkyne (phenyl acetylene) to give substituted pyridine products. Fundamental reactivity and selectivity studies are complemented by the synthesis of the polycyclic ergot alkaloid natural product xylanigripone A.

PH-Responsive Micelles Containing Quinine Functionalities Enhance Intracellular Gene Delivery and Expression.

Quinine is a promising building block for creating polymer carriers for intracellular nucleic acid delivery. This is due to its ability to bind to genetic material through intercalation and electrostatic interactions and the balance of hydrophobicity and hydrophilicity dependent on the pH/charge state. Yet, studies utilizing cinchona alkaloid natural products in gene delivery are limited. Herein, we present the incorporation of a quinine functionalized monomer (Q) into block polymer architectures to form self-assembled micelles for highly efficient gene delivery. Q was incorporated into the core and/or the shell of the micelles to introduce the unique advantages of quinine to the system. We found that incorporation of Q into the core of the micelle resulted in acid-induced disassembly of the micelle and a boost in transfection efficiency by promoting endosomal escape. This effect was especially evident in the cancerous cell line, A549, which has a more acidic intracellular environment. Incorporation of Q into the shell of the micelles resulted in intercalative binding to the genetic payload as well as larger micelle-DNA complexes (micelleplexes) from the hydrophobicity of Q in the shell. These factors enable the micelleplexes to be more resistant to serum and have more persistent protein expression post-transfection. Overall, this study is the first to demonstrate the benefits of including quinine functionalities into self-assembled micelles for highly efficient gene delivery and presents a platform for inclusion of other natural products with similar properties into micellar systems.

Grignard Reagent Addition to Pyridinium Salts: A Catalytic Approach to Chiral 1,4-Dihydropyridines.

Catalytic dearomatization of pyridinium salts is a powerful technique for constructing chiral N-heterocycles, which are crucial in alkaloid natural products and drugs. Despite its potential, progress in metal-catalyzed asymmetric dearomatization of pyridinium derivatives has been limited. Here, we present the enantioselective 1,4-dearomatization of pyridinium salts using Grignard reagents and chiral copper catalysis. This approach yields enantioenriched functionalized 1,4-dihydropyridines. Experimental kinetic isotope effects and density functional theory calculations provide insights into the reaction mechanism, regio- and enantioselectivity, and the rate-limiting step.

Catalytic enantioselective nitrone cycloadditions enabling collective syntheses of indole alkaloids

Tetrahydro-β-carboline skeletons are prominent and ubiquitous in an extraordinary range of indole alkaloid natural products and pharmaceutical compounds. Powerful synthetic approaches for stereoselective synthesis of tetrahydro-β-carboline skeletons have immense impacts and have attracted enormous attention. Here, we outline a general chiral phosphoric acid catalyzed asymmetric 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide type nitrone that enables access to three types of chiral tetrahydro-β-carbolines bearing continuous multi-chiral centers and quaternary chiral centers. The method displays different endo/exo selectivity from traditional nitrone chemistry. The distinct power of this strategy has been illustrated by application to collective and enantiodivergent total syntheses of 40 tetrahydro-β-carboline-type indole alkaloid natural products with divergent stereochemistry and varied architectures.

Verazine biosynthesis from simple sugars in engineered Saccharomyces cerevisiae

Steroidal alkaloids are FDA-approved drugs (e.g., Zytiga) and promising drug candidates/leads (e.g., cyclopamine); yet many of the ≥697 known steroidal alkaloid natural products remain underutilized as drugs because it can be challenging to scale their biosynthesis in their producing organisms. Cyclopamine is a steroidal alkaloid produced by corn lily (Veratrum spp.) plants, and it is an inhibitor of the Hedgehog (Hh) signaling pathway. Therefore, cyclopamine is an important drug candidate/lead to treat human diseases that are associated with dysregulated Hh signaling, such as basal cell carcinoma and acute myeloid leukemia. Cyclopamine and its semi-synthetic derivatives have been studied in (pre)clinical trials as Hh inhibitor-based drugs. However, challenges in scaling the production of cyclopamine have slowed efforts to improve its efficacy and safety profile through (bio)synthetic derivatization, often limiting drug development to synthetic analogs of cyclopamine such as the FDA-approved drugs Odomzo, Daurismo, and Erivedge. If a platform for the scalable and sustainable production of cyclopamine were established, then its (bio)synthetic derivatization, clinical development, and, ultimately, widespread distribution could be accelerated. Ongoing efforts to achieve this goal include the biosynthesis of cyclopamine in Veratrum plant cell culture and the semi-/total chemical synthesis of cyclopamine. Herein, this work advances efforts towards a promising future approach: the biosynthesis of cyclopamine in engineered microorganisms. We completed the heterologous microbial production of verazine (biosynthetic precursor to cyclopamine) from simple sugars (i.e., glucose and galactose) in engineered Saccharomyces cerevisiae (S. cerevisiae) through the inducible upregulation of the native yeast mevalonate and lanosterol biosynthetic pathways, diversion of biosynthetic flux from ergosterol (i.e., native sterol in S. cerevisiae) to cholesterol (i.e., biosynthetic precursor to verazine), and expression of a refactored five-step verazine biosynthetic pathway. The engineered S. cerevisiae strain that produced verazine contains eight heterologous enzymes sourced from seven different species. Importantly, S. cerevisiae-produced verazine was indistinguishable via liquid chromatography-mass spectrometry from both a commercial standard (Veratrum spp. plant-produced) and Nicotiana benthamiana-produced verazine. To the best of our knowledge, this is the first report describing the heterologous production of a steroidal alkaloid in an engineered yeast. Verazine production was ultimately increased through design-build-test-learn cycles to a final titer of 83 ± 3 μg/L (4.1 ± 0.1 μg/g DCW). Together, this research lays the groundwork for future microbial biosynthesis of cyclopamine, (bio)synthetic derivatives of cyclopamine, and other steroidal alkaloid natural products.

Total Synthesis of Tabernanthine and Ibogaline: Rapid Access to Nosyl Tryptamines

AbstractWe describe the first total syntheses of tabernanthine and ibogaline. Entry to these iboga alkaloid natural products is enabled by a thermal coupling of indoles and aziridines to furnish the requisite nosyl tryptamine starting materials. This route features a Friedel‐Crafts type alkylation to form the key indole‐isoquinuclidine C−C bond. Finally, a regio‐ and diastereoselective hydroboration‐oxidation enables C−N bond formation to close the isoquinuclidine ring system and deliver tabernanthine and ibogaline in 10 and 14 % yield respectively. Both syntheses were completed in eight steps.

Ru(II)-Catalyzed C(sp2)-H Activation Annulation: Synthesis of Fluorescent Benzoisoquinolonyl Acetate/Peptides from N-Arylamides and Ethyne at Room Temperature.

Benzoisoquinolones are aryl ring extended isoquinolinone derivatives, which are constituents of alkaloid natural products. This report describes the synthesis of novel benzoisoquinolone amino acid/peptide derivatives from the respective N-aryl amino esters/peptides through Ru-catalyzed C(sp2)-H annulation at room temperature. The N-terminal amide acts as an intrinsic directing group and coordinates with the active Ru(II) catalyst for the C-H bond activation and annulation of the aryl ring to produce benzoisoqunolone derivatives. Importantly, these benzoisoquinolinones exhibit fluorescence (QY ∼35%) in protic polar solvents, possibly due to charge transfer, and exhibit cell internalization to the cell nucleus without any significant cytotoxicity to human cell lines (HEK293T). Hence, our results are exceptional to transform standard amino acids/peptides into fluorescent peptides at room temperature in the late stage, which could be applicable for tracking specific target peptides by fluorescence microscopy.

Synthesis and Antibacterial Studies of Phenethylamine Alkaloid Natural Products Along with Their Analogues: Discolin A, B, E and Bacillimidazole B

AbstractThe first total synthesis of phenethylamine alkaloid based natural products discolin A, B, E and bacillimidazole B is reported, which were isolated from marine sea bacteria Tenacibaculum discolor sv11 and marine sponge. Total syntheses of discolin A, B, E and bacillimidazole B are achieved in two linear steps including condensation reaction and N-alkylation reaction with an overall yield of 68%, 35%, 65%, and 32%, respectively. A total of 24 analogues are prepared with moderate to excellent yield. All the natural products and their analogues were screened for antibacterial activity. The most active compound showed an IC50 of 122.1 nM against P. aeruginosa.

An emerging strategy towards the iodine catalyzed synthesis of Streptindole and its derivatives in water medium.

In this study, we propose an alternative metal‐free methodology for the synthesis of Streptindole and its derivatives. This approach employs economically viable and easily handled molecular iodine (I2) as the catalyst in an aqueous medium. The method demonstrates remarkable tolerance towards a diverse array of functional groups. The versatility of the developed protocol is highlighted by its application in the efficient total syntheses of the alkaloid natural products, Streptindole and Arsindoline B accomplished in a single step from indole. Furthermore, the methodology is also useful for the synthesis of pharmaceutically significant compounds, specifically anti‐TMV agents (5c, 5d, and 5e) and an anticancer agent (5f). Control experiments have been carried out to study the plausible catalytic cycle by finding the key intermediates. The experimental findings support the mechanistic pathway involving halogen bond activation in molecular iodine catalysis

Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives

Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.

Controllable skeletal reorganizations in natural product synthesis.

Covering: 2016 to 2023The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C-C and C-heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.

‘Cephalandole A’ analogues as a new class of antioxidant agents: Design, microwave-assisted synthesis, bioevaluation, SAR and in silico studies

Herein, a novel series of natural product alkaloid ‘Cephalandole A’ analogues 19a-y, and 20a-d were rapidly synthesised under microwave irradiation conditions using PTSA in catalytic amount dissolved in acetonitrile at 90 °C for 15 min. The developed one-pot protocol is operationally simple, rapid (15 min) and furnished the target analogues in up to 90 % yield. All the synthesised analogues of Cephalandole A were evaluated for their in vitro antioxidant activity using DPPH free-radical scavenging and FRAP assays. The in vitro studies of DPPH radical scavenging assay provided 19a (IC50 = 11.87 ± 0.14 µg/mL), 19f (IC50 = 16.34 ± 0.27 µg/mL), 19n (IC50 = 15.37 ± 0.11 µg/mL) and 20a (IC50 = 14.54 ± 0.31 µg/mL) respectively, as the most active compounds of the series. In addition, the analogous 19d (556.3 ± 13.1 µM) and 19v (551.9 ± 14.2 µM) showed promising activity in FRAP assay. However, the standard reference drug ascorbic acid showed an IC50 value of 4.57 µg/mL in the DPPH assay, and BHT showed C0.5FRAP = 546.0 ± 13.6 μM in the FRAP assay. In silico studies were performed to validate the wet results. To the best of our knowledge, this is the first report demonstrating ‘Cephalandole A’ analogues as a new class of antioxidant agents.

Cinchona Alkaloid Polymers Demonstrate Highly Efficient Gene Delivery Dependent on Stereochemistry, Methoxy Substitution, and Length.

Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate. Cinchona alkaloids are an attractive monomer class for gene delivery applications, given their ability to bind to DNA via both electrostatics and intercalation. To uncover the structure-activity profile of the system, four structurally similar cinchona alkaloids were incorporated into polymers: quinine, quinidine, cinchonine, and cinchonidine. These polymers differed in the chain length, the presence or absence of a pendant methoxy group, and stereochemistry, all of which were found to alter gene delivery performance and the ways in which the polymers overcome biological barriers to transfection. Longer polymers that contained the methoxy-bearing cinchona alkaloids (i.e., quinine and quinidine) were found to have the best performance. These polymers exhibited the tightest DNA binding, largest and most abundant DNA-polymer complexes, and best endosomal escape thanks to their increased buffering capacity and closest nuclear proximity of the payload. Overall, this work highlights the remarkable efficiency of polymer systems that incorporate cinchona alkaloid natural products while demonstrating the profound impact that small structural changes can have on overcoming biological hurdles associated with gene delivery.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

Alkaloid diversity expansion of a talent fungus Penicillium raistrichii through OSMAC-based cultivation.

Alkaloidal natural products are attractive for their broad spectrum of pharmaceutical bioactivities. In the present work, the highly productive saline soil derived fungus, Penicillium raistrichii, was subjected to the strategy of OSMAC (one strain many compounds) with changes of cultivation status. Then, the work-flow led to the expansion of the alkaloid chemical diversity and subsequently induced the accumulation of four undescribed alkaloids, named raistrimides A-D (1-4), including three β-carbolines (1-3), one 2-quinolinone (4), and one new natural product, 2-quinolinone (5), along with five known alkaloid chemicals (6-10). A set of NMR techniques including 1H, 13C, HSQC and HMBC, along with other spectroscopic data of UV-Vis, IR and HRESIMS, were introduced to assign the plain structures of compounds 1-10. The absolute configuration of 1-3 were elucidated by means of X-ray crystallography or spectroscopic analyses on optical rotation values and experimental electronic circular dichroism (ECD) data. In addition, it was the first report on the confirmation of structures of 6, 7 and 9 by X-ray crystallography data. The micro-broth dilution method was applied to evaluate antimicrobial effect of all compounds towards Staphylococcus aureus, Escherichia coli, and Candida albicans. The results indicated compounds 1, 3 and 4 to be bioactive, which may be potential for further development of anti-antimicrobial agents. The finding in this work implied that OSMAC strategy was a powerful and effective tool for promotion of new chemical entities from P. raistrichii.

Neuroprotective Properties of Berberine: Molecular Mechanisms and Clinical Implications.

Berberine (BBR), an isoquinoline alkaloid natural product, is isolated primarily from Coptis chinensis and other Berberis plants. BBR possesses various bioactivities, including antioxidant, anti-inflammation, anticancer, immune-regulation, and antimicrobial activities. Growing scientific evidence underscores BBR's substantial neuroprotective potential, prompting increased interest and scrutiny. In this comprehensive review, we elucidate the neuroprotective attributes of BBR, delineate the underlying molecular mechanisms, and assess its clinical safety and efficacy. The multifaceted molecular mechanisms responsible for BBR's neuroprotection encompass the attenuation of oxidative stress, mitigation of inflammatory responses, inhibition of apoptotic pathways, facilitation of autophagic processes, and modulation of CYP450 enzyme activities, neurotransmitter levels, and gut microbiota composition. Furthermore, BBR engages numerous signaling pathways, including the PI3K/Akt, NF-κB, AMPK, CREB, Nrf2, and MAPK pathways, to confer its neuroprotective effects. This comprehensive review aims to provide a substantial knowledge base, stimulate broader scientific discourse, and facilitate advancements in the application of BBR for neuroprotection.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

BiBr3‐Mediated Intramolecular Aza‐Prins Cyclization of Aza‐Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids

AbstractAn intramolecular aza‐Prins cyclization of aza‐Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9‐azabicyclo[3.3.1]nonanes (9‐ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza‐Prins cyclization include 1,1‐disubstituted alkenes, 1,2‐disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (−)‐suaveoline (1), (−)‐norsuaveoline (2), (−)‐macrophylline (3), (+)‐normacusine B (4), (+)‐Na‐methyl‐16‐epipericyclivine (5) and (+)‐affinisine (6) in a total of 9–14 steps. This study significantly expands the synthetic utility of the aza‐Achmatowicz rearrangement, and the strategy (aza‐Achmatowicz/aza‐Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent.

TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.

Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone.

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (-)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.