Class Of Natural Products Research Articles

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A

AbstractKopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure‐unit‐based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza‐Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all‐carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α‐hydroxyketone moiety, and a bioinspired retro‐Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A.

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Reaction intensification for biocatalytic production of polyphenolic natural product di-C-β-glucosides.

Polyphenolic aglycones featuring two sugars individually attached via C-glycosidic linkage (di-C-glycosides) represent a rare class of plant natural products with unique physicochemical properties and biological activities. Natural scarcity of such di-C-glycosides limits their use-inspired exploration as pharmaceutical ingredients. Here, we show a biocatalytic process technology for reaction-intensified production of the di-C-β-glucosides of two representative phenol substrates, phloretin (a natural flavonoid) and phenyl-trihydroxyacetophenone (a phenolic synthon for synthesis), from sucrose. The synthesis proceeds via an iterative two-fold C-glycosylation of the respective aglycone, supplied as inclusion complex with 2-hydroxypropyl β-cyclodextrin for enhanced water solubility of up to 50 mmol/L, catalyzed by a kumquat di-C-glycosyltransferase (di-CGT), and it uses UDP-Glc provided in situ from sucrose by a soybean sucrose synthase, with catalytic amounts (≤3 mol%) of UDP added. Time course analysis reveals the second C-glycosylation as rate-limiting (0.4-0.5 mmol/L/min) for the di-C-glucoside production. With internal supply from sucrose keeping the UDP-Glc at a constant steady-state concentration (≥50% of the UDP added) during the reaction, the di-C-glycosylation is driven to completion (≥95% yield). Contrary to the mono-C-glucoside intermediate which is stable, the di-C-glucoside requires the addition of reducing agent (10 mmol/L 2-mercaptoethanol) to prevent its decomposition during the synthesis. Both di-C-glucosides are isolated from the reaction mixtures in excellent purity (≥95%), and their expected structures are confirmed by NMR. Collectively, this study demonstrates efficient glycosyltransferase cascade reaction for flexible use in natural product di-C-β-glucoside synthesis from expedient substrates.

Asymmetric synthesis of the functionalized A/E bicyclic fragment of the C<sub>19</sub>-diterpenoid alkaloids

<p indent="0mm">The C₁₉-diterpenoid alkaloids belong to a class of natural products with significant biological activities. These molecules are structurally characterized by complex cage-like skeletons and dense functional substituents. The efficient preparation of the A/E aza-bridged ring system, which is ubiquitous in C₁₉-diterpenoid alkaloids, would lay an important foundation for their total synthesis. This paper reports a new asymmetric synthesis of the functionalized A/E bicyclic fragment of the C₁₉-diterpenoid alkaloids, featuring desymmetrization, diastereoselective allylaltion, aldol hydroxymethylation, and reductive amination as key steps.

Biogenesis-Inspired Synthesis of Penicillitone

AbstractThe biogenesis-inspired synthesis of the structurally unique 15(14→11)abeo-steroid penicillitone starting from commercially available ergosterol is reported. Key to the strategy is an intramolecular vinylogous aldol reaction of a 14,15-secoergostane obtained from the previously reported 14,15-secosteroid platform. Since a similar intermediate has been employed to access the strophasterol class of natural products, this work points at a possible biosynthetic connection between penicillitone and the strophasterols.

Diverse enzymatic chemistry for propionate side chain cleavages in tetrapyrrole biosynthesis.

This mini-review describes various enzymes involved in the propionate side chain cleavages during the biosynthesis of tetrapyrrole cofactors and secondary metabolites.

Macamide B suppresses lung cancer progression potentially via the ATM signaling pathway.

Macamides are a class of bioactive natural products obtained from Lepidium meyenii (maca), which have been reported to exert inhibitory activity in cancer. However, their role in lung cancer is currently unknown. In the present study, macamide B was shown to inhibit the proliferation and invasion of lung cancer cells, as determined by Cell Counting Kit-8 and Transwell assays, respectively. By contrast, macamide B induced cell apoptosis, as determined by Annexin V-FITC assay. Moreover, combined treatment with macamide B and olaparib, an inhibitor of poly (ADP-ribose) polymerase, further suppressed the proliferation of lung cancer cells. At the molecular level, the expression of ataxia-telangiectasia mutated (ATM), RAD51, p53 and cleaved caspase-3 were significantly increased by macamide B, as determined by western blotting, whereas the expression levels of Bcl-2 were decreased. By contrast, when ATM expression was knocked down by small interfering RNA technology in A549 cells treated with macamide B, the expression levels of ATM, RAD51, p53 and cleaved caspase-3 were reduced, whereas those of Bcl-2 were increased. Consistently, cell proliferation and invasive ability were partially rescued by ATM knockdown. In conclusion, macamide B inhibits lung cancer progression by inhibiting cell proliferation and invasion, and inducing apoptosis. Furthermore, macamide B may participate in regulating the ATM signaling pathway. The present study provides a potential new natural drug for treating patients with lung cancer.

Talaroclauxins A and B: Duclauxin-ergosterol and duclauxin-polyketide hybrid metabolites with complicated skeletons from Talaromyces stipitatus

Talaroclauxins A and B (1 and 2), two novel duclauxin hybrids, were obtained from Talaromyces stipitatus, along with three new (3−5) and one known analogue (6). Their structures were determined by NMR spectroscopy, HRESIMS, single-crystal X-ray diffraction, and quantum chemical calculations. Compound 1 is the first example of duclauxin-ergosterol hybrid featuring an unprecedented dodecacyclic ring system formed via a [4 + 2] cycloaddition, while compound 2, bearing an unusual 6/6/6/5/6/6/6/6 ring system, is a new member of the rare duclauxin-polyketide hybrid class of natural products. Plausible biosynthetic pathways for 1−6 are proposed. Compound 5 displayed moderate neuroprotective effects in glutamate sodium-induced SH-SY5Y cells.

Fragment Coupling Approach to Diaporthein B.

Pimarane diterpenes are produced by a diverse array of plants, fungi, and bacteria. Many members of this family possess antimicrobial and antiproliferative activities. The pimarane diterpenes are characterized by a tricyclic carbon scaffold comprising three fused six-membered rings and at least three quaternary centers. Here, we describe two convergent, fragment-based strategies toward the synthesis of diaporthein B (3), one of the most highly oxidized pimarane diterpenes. The first approach provided access to the tricyclic carbon scaffold of the target and featured a highly diastereoselective fragment coupling, a novel carbonylative Stille cross-coupling to directly access an α-hydroxyketone from a vinyl iodide, and a tandem aldol cyclization-deprotection cascade. The second route utilized a diastereoselective 1,4-addition of a silyloxyfuran to an unsaturated ketone, followed by an epoxidation-ring opening sequence, to access a highly oxidized intermediate containing two elaborated cyclohexane rings. The chemistry developed herein may ultimately be useful in an eventual synthesis of this class of natural products.

Synthetic Studies on Tetracyclic Diquinane Lycopodium Alkaloids Magellanine, Magellaninone and Paniculatine.

(-)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer's and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons.

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives.

Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-ᴅ-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria and its absence in humans make all its enzymes suitable targets for the development of novel antibacterial drugs. (E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), the last intermediate of this pathway, is a natural ligand for the human Vγ9Vδ2 T cells and the most potent natural phosphoantigen known to date. Moreover, 5-hydroxypentane-2,3-dione, a metabolite produced by Escherichia coli 1-deoxy-ᴅ-xylulose 5-phosphate synthase (DXS), the first enzyme of the MEP pathway, structurally resembles (S)-4,5-dihydroxy-2,3-pentanedione, a signal molecule implied in bacterial cell communication. In this review, we shed light on the diversity of potential uses of the MEP pathway in antibacterial therapies, starting with an overview of the antibacterials developed for each of its enzymes. Then, we provide insight into HMBPP, its synthetic analogs, and their prodrugs. Finally, we discuss the potential contribution of the MEP pathway to quorum sensing mechanisms. The MEP pathway, providing simultaneously antibacterial drug targets and potent immunostimulants, coupled with its potential role in bacterial cell-cell communication, opens new therapeutic perspectives.

Synthesis of Stereoisomeric Simplified Analogs of Alotaketals toward the Elucidation of the Structural Requirements of Protein Kinase C Isozyme-Selective Binding.

A set of four stereoisomeric compounds were designed and synthesized as ligands of protein kinase C (PKC). The compounds were simplified analogs of the alotaketals, a class of natural products that were predicted to be ligands of PKC by computational screening. Bioassays revealed that the orientation of the alkyl side chain of the analogs was important for PKC binding and that the stereochemistry of the fused ring moiety influenced the PKC isozyme selectivity.

The Chemical Space of Terpenes: Insights from Data Science and AI.

Terpenes are a widespread class of natural products with significant chemical and biological diversity, and many of these molecules have already made their way into medicines. In this work, we employ a data science-based approach to identify, compile, and characterize the diversity of terpenes currently known in a systematic way, in a total of 59,833 molecules. We also employed several methods for the purpose of classifying terpene subclasses using their physicochemical descriptors. Light gradient boosting machine, k-nearest neighbours, random forests, Gaussian naïve Bayes and Multilayer perceptron were tested, with the best-performing algorithms yielding accuracy, F1 score, precision and other metrics all over 0.9, thus showing the capabilities of these approaches for the classification of terpene subclasses. These results can be important for the field of phytochemistry and pharmacognosy, as they allow the prediction of the subclass of novel terpene molecules, even when biosynthetic studies are not available.

Chalcones: Potential Chemotherapeutic Compounds and Educational Tools for Closing the Loop in STEM.

ConspectusThe study discussed herein describes the synthesis of halogenated chalcones as potential chemotherapeutics. The synthesis work was conducted by undergraduate students participating in an Organic Chemistry II laboratory course at Tuskegee University, while the biological assays were conducted by students enrolled in a Molecular Biology I laboratory course. Chalcones were synthesized via aldol condensation and purified from hot ethanol. The impetus for the work was the fact that Tuskegee University sits positioned within the Black Belt of Alabama which, in addition to being an area of fertile soil and excellent farmland, is also an area rife with health disparities that particularly affect African-Americans. Breast cancer, specifically triple-negative breast cancer, affects African-American women at a higher rate than any other ethnic group. The work described herein addresses a practical problem [teaching undergraduate students about the interface of synthetic techniques, synthesis of specific classes of compounds, functional groups, and their relation to biological activity], as well an existential problem [the prevalence of breast cancer among African-American women, and the need to develop targeted treatments]. One of the chief aims of this approach of integrating these ideas into our laboratory courses was to facilitate the understanding of translational science, i.e. taking chalcones from benchtop to potential therapies for breast cancer. Another aim of the current approach was to, in essence, create a research problem based course and concomitantly use the results of the experiments performed in the course as a way to address the dearth of research funding that HBCUs typically receive. The pharmacological activities of chalcones and their derivatives are well documented. They are an important class of natural products that occur in edible plant derivatives such as spices, teas, fruits and various vegetables. In vitro studies have shown that chalcones inhibit proliferation of breast cancer cells by inducing apoptosis and blocking cell progression. The synthesis of chalcones with aromatic substituents has been investigated, and electron rich chalcones, i.e., chalcones with donors attached to the aromatic rings, have been studied extensively. The effect that adding electron withdrawing groups to the chalcone structural motif has on the antiproliferation ability of chalcones had been only minimally investigated at the time that our studies were being conducted. We examined the introduction of chlorine to the aromatic system of the chalcone and how these electron withdrawing substituents affect the chalcone's antiproliferative ability. It was discovered that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one inhibited MDA-MB-231 cell progression in a dose dependent manner and outperformed the unsubstituted (E)-1,3-diphenyl-2-propen-1-one (1) at concentrations ranging from 0 μg/mL to 20 μg/mL. Cell death was determined by MTT assay.

Cell Factory for Phenylnaphthacenoid Polyketide Production

Covering 2009–2022. Phenylnaphthacenoid polyketides have gained significant interest in recent years owing to their potent antibacterial and anticancer activities. Notably, more than 100 members of this class of natural products have been discovered from various Streptomyces species by different research groups including ours over the last 13 years. This review summarizes the current knowledge of the discovery, chemical diversity, and bioactivity of phenylnaphthacenoid polyketides. The current review also highlights the cell factory for phenylnaphthacenoid production: (1) native strains, (2) mutant strains, (3) heterologous expression, and (4) biocatalytic halogenations. Furthermore, current challenges and future opportunities are also presented as a guide for researchers to explore them more purposefully.

Structural diversity-guided optimization of carbazole derivatives as potential cytotoxic agents.

Carbazole alkaloids, as an important class of natural products, have been widely reported to have extensive biological activities. Based on our previous three-component reaction to construct carbazole scaffolds, we introduced a methylene group to provide a rotatable bond, and designed series of carbazole derivatives with structural diversity including carbazole amide, carbazole hydrazide and carbazole hydrazone. All synthesized carbazole derivatives were evaluated for their in vitro cytotoxic activity against 7901 (gastric adenocarcinoma), A875 (human melanoma) and MARC145 (African green monkey kidney) cell lines. The preliminary results indicated that compound 14a exhibited high inhibitory activities on 7901 and A875 cancer cells with the lowest IC50 of 11.8 ± 1.26 and 9.77 ± 8.32μM, respectively, which might be the new lead compound for discovery of novel carbazole-type anticancer agents.

Low Energy Collision-Induced Dissociation of Azepine Pictet-Spengler Adducts of Nω-Methylserotonin.

Cimitrypazepines are a class of natural products produced by Pictet-Spengler condensation of Nω-methylserotonin and aldehydes in a manner that produces a seven-membered azepine ring. In this study, the fragmentation behavior of this class of molecules under low-energy CID was investigated in detail. Proposed mechanisms of fragmentation were supported by deuterium labeling and DFT calculations. Loss of methylamine and methylenimine were dominant fragmentation pathways of analogs containing an aliphatic side chain. Loss of methylenimine was found to proceed via unusual methyl cation transfer. Fragmentation of analogs containing an aromatic side chain was strongly influenced by the nature of the substituents and proceeded via a novel retro-Pictet-Spengler pathway and involvement of ion-neutral complexes. In some cases, a gas-phase interconversion between the azepine and β-carboline ring was observed during fragmentation. Detailed analysis of fragmentation behavior provided in this study will serve as a valuable guide for the discovery of new analogs from natural sources.

Total Synthesis of Floyocidin B: 4,5-Regioselective Functionalization of 2-Chloropyridines

The recently discovered natural product (NP) (+)-floyocidin B with antimicrobial activity against Mycobacterium tuberculosis displays a hitherto unknown dihydroisoquinolinone scaffold in the class of the epoxyquinone NPs. The 4,5-regioselective functionalization of 2-chloropyridines was identified as a suitable strategy leading to the total syntheses of (+)-floyocidin B and analogs. In this paper, we present the long and winding evolution process to the final synthetic pathway, including model systems for route scouting and elucidation of side products, which enabled us to understand the unique reactivity of this unprecedented scaffold. A special focus was laid on method studies with different 2-chloropyridines, disclosing an unexpected effect of the 2-chloro substituent on the regioselectivity compared to 2-unsubstituted or carbon-substituted pyridines. Finally, a head-to-head comparison with the previously described synthesis of all four stereoisomers of the NP (−)-avicennone C revealed significant differences in the reactivity of these structurally closely related scaffolds.

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis.

Leishmaniasis is a neglected tropical disease, affecting more than 350 million people globally. However, there is currently no vaccine available against human leishmaniasis, and current treatment is hampered by high cost, side-effects, and painful administration routes. It has become a United Nations goal to end leishmaniasis epidemics by 2030, and multitarget drug strategy emerges as a promising alternative. Among the multitarget compounds, flavonoids are a renowned class of natural products, and a structurally diverse library can be prepared through organic synthesis, which can be tested for biological effectiveness. In this study, we synthesised 17 flavonoid analogues using a scalable, easy-to-reproduce, and inexpensive method. All synthesised compounds presented an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y enzymes, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b were found to be effective against all isoforms. Furthermore, their intermolecular interactions were also investigated through a molecular modelling study. These compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. These results are pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Moreover, compounds have been shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

Manganese‐Catalyzed Transfer Hydrodebromination of Aryl Bromides with Ethanol

AbstractA convenient PNP pincer manganese catalyzed transfer hydrogenation of bromides to corresponding debrominated aryl compounds using ethanol as the hydrogen sources is reported. Importantly, the application of biomass‐derived ethanol highlights the sustainability of the methodology. The use of 6‐phenyl substituted triazine‐based PiprN5Pipr manganese pincer catalyst allows for the debromination of various aryl bromides with good yields. Notably, the process also occurs with bromides derived from several classes of natural products and bioactive compounds, such as citronellol, diacetone fructose, cholesterol, and vitamin E.