Design, Synthesis, and Antifungal Activities of Phenylpyrrole Analogues Based on Alkaloid Lycogalic Acid.

Plant diseases caused by pathogenic fungi seriously affect the yield and quality of crops, cause huge economic losses, and pose a considerable threat to global food security. Phenylpyrrole analogues were designed and synthesized based on alkaloid lycogalic acid. All target compounds were characterized by 1H NMR, 13C NMR, and HRMS. Their antifungal activities against seven kinds of phytopathogenic fungi were evaluated. The results revealed that most compounds had broad-spectrum fungicidal activities at 50 µg/mL; 14 compounds displayed more than 60% fungicidal activities against Rhizoctonia cerealis and Sclerotinia sclerotiorum, and in particular, the fungicidal activities of compounds 8g and 8h against Rhizoctonia cerealis were more than 90%, which could be further developed as lead agents for water-soluble fungicides. The molecular docking results indicate that compounds 8g and 8h can interact with 14α-demethylase (RcCYP51) through hydrogen bonding with strong affinity.

Alkaloid-Based Isoxazolylureas: Synthesis and Effect in Combination with Anticancer Drugs on C6 Rat Glioma Model Cells.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

Identification by Synthesis: Imidacins, Urocanate-Derived Alkaloids from the Myxobacterium Stigmatella aurantiaca.

Innovative discovery approaches such as genome-mining and metabolomics-inspired methods have reshaped the natural product research field, complementing traditional bioactivity-based screens and allowing hitherto unseen compounds to be uncovered from previously investigated producers. In line with these trends, we report here imidacins, a novel class of secondary metabolites specific to the myxobacterial genus Stigmatella. A combination of secondary metabolome analysis, genome-mining techniques, spectroscopic analysis, and finally total synthesis was used to allow structure elucidation. Imidacins are urocanate-derived aliphatic acids with an adjacent cyclopropane moiety, structural features unprecedented in natural products to date.

Design and synthesis of matrine derivatives for anti myocardial ischemia-reperfusion injury by promoting angiogenesis.

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.

Discovery of Sophoridine α-Aryl Propionamide Derivative ZM600 as a Novel Antihepatic Fibrosis Agent.

Hepatic stellate cells (HSCs) activation is a key event in the development of liver fibrosis, and blockage of the activation of HSCs has been shown to alleviate liver fibrosis. Sophoridine, a bioactive alkaloid found in many Chinese herbs, exhibits a broad spectrum of pharmacological effects, but its activities are not strong. In this study, a series of structurally modified derivatives of sophoridine were designed and synthesized. Among them, sophoridine α-aryl propionamide derivative ZM600 displayed a significant inhibitory effect on the activation of HSCs. The in vivo experiment demonstrated that ZM600 markedly ameliorated carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced liver fibrosis with a significant improvement of extracellular matrix deposition. Mechanism investigations revealed that ZM600 specifically inhibited the activation of NF-κB, PI-3K/AKT, and TGF-ß/Smads signaling pathways. These results suggest that ZM600 has a protective effect on liver fibrosis, which provides a new candidate for the treatment of liver fibrosis.

Evolution of a Synthetic Strategy toward the Syntheses of Bis-tetrahydroisoquinoline Alkaloids.

ConspectusThe bis-tetrahydroisoquinoline (bis-THIQ) natural products represent a medicinally important class of isoquinoline alkaloids that exhibit broad biological activities with particularly potent antitumor properties, as exemplified by the two U.S. FDA approved molecules trabectidin and lurbinectedin. Accordingly, other members within the bis-THIQ family have emerged as prime targets for synthetic chemists, aiming to innovate an orthogonal chemical production of these compounds. With the ability of these complementary strategies to reliably and predictably manipulate molecular structures with atomic precision, this should allow the preparation of synthetic derivatives not existing in nature as new drug leads in the development of novel medicines with desired biological functions.Beyond the biological perspective, bis-THIQ natural products also possess intricate and unique structures, serving as a source of intellectual stimulation for synthetic organic chemists. Within our laboratory, we have developed an integrated program that combines reaction development and target-directed synthesis, leveraging the architecturally complex molecular framework of bis-THIQ natural products as a driving force for the advancement of novel reaction methodologies. In this Account, we unveil our synthetic efforts in a comprehensive story, describing how our synthetic strategy toward bis-THIQ natural products, specifically jorunnamycin A and jorumycin, has evolved over the course of our studies through our key transformations comprising (a) the direct functionalization of isoquinoline N-oxide to prepare the bis-isoquinoline (bis-IQ) intermediate, (b) the diastereoselective and enantioselective isoquinoline hydrogenation to forge the pentacyclic skeleton of the natural product, and (c) the late-stage oxygenation chemistry to adjust the oxidation states of the A- and E-rings. First, we detail our plan in utilizing the aryne annulation strategy to prepare isoquinoline fragments for the bis-THIQ molecules. Faced with unpromising results in the direct C-H functionalization of isoquinoline N-oxide, we lay out in this Account our rationale behind the design of each isoquinoline coupling partner to overcome these challenges. Additionally, we reveal the inspiration for our hydrogenation system, the setup of our pseudo-high-throughput screening, and the extension of the developed hydrogenation protocols to other simplified isoquinolines.In the context of non-natural bis-THIQ molecules, we have successfully adapted this tandem coupling/hydrogenation approach in the preparation of perfluorinated bis-THIQs, representing the first set of electron-deficient non-natural analogues. Finally, we include our unsuccessful late-stage oxygenation attempts prior to the discovery of the Pd-catalyzed C-O cross-coupling reaction. With this full disclosure of the chemistry developed for the syntheses of bis-THIQs, we hope our orthogonal synthetic tactics will provide useful information and serve as an inspiration for the future development of bis-THIQ pharmaceuticals.

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Total Syntheses of the Structures Assigned to Denigrins A, B, C, F, and G, 3,4-Diaryl-Pyrrole and -Pyrrolidinone Alkaloids, and the Conversion of Congener B into the Co-metabolite Spirodactylone.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3, 6, and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B (2). The structure, 3, assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone (16), while treating the corresponding permethyl ether 15 with PIFA/BF3·Et2O provides compound 20, embodying an isomeric framework.

Total Synthesis of Lissodendoric Acid A.

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Flexible and Convergent Enantioselective Total Synthesis of (R)-Juglanaloids A and B: Two Phthalide Spiro Alkaloids with Potential Alzheimer's Disease Inhibitory Activity.

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.

Synthesis and Dopaminergic Neuroprotective Activity of the Proposed Structure of Bassiamide A, a Caffeamide Alkaloid Derived from Bassia Indica Wight.

Herein, we describe the synthesis of the proposed structure of the caffeamide alkaloid bassiamide A. The amide moiety of bassiamide A was readily formed via an amide coupling reaction between caffeic acid and the known N-(3-aminopropyl)-3-methylbutanamide. However, the spectral data of the synthesized bassiamide A did not agree with that of a previous study. The structure of the synthesized bassiamide A was confirmed using combined two-dimensional NMR analysis. Extended analyses of the bioactivity of the synthesized bassiamide A revealed its efficacy in protecting dopaminergic neurons from MPP+-induced neurotoxicity in Caenorhabditis elegans. Additionally, treatment with bassiamide A notably ameliorated the impaired food-sensing ability and locomotion of Caenorhabditis elegans, suggesting a protective effect on the functionality of dopaminergic neurons.

Dopamine-Derived Guanidine Alkaloids from a Didemnidae Tunicate: Isolation, Synthesis, and Biological Activities.

Mellpaladines A-C (1-3) and dopargimine (4) are dopamine-derived guanidine alkaloids isolated from a specimen of Palauan Didemnidae tunicate as possible modulators of neuronal receptors. In this study, we isolated the dopargimine derivative 1-carboxydopargimine (5), three additional mellpaladines D-F (6-8), and serotodopalgimine (9), along with a dimer of serotonin, 5,5'-dihydroxy-4,4'-bistryptamine (10). The structures of these compounds were determined based on spectrometric and spectroscopic analyses. Compound 4 and its congeners dopargine (11), nordopargimine (15), and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)ethan-1-amine (16) were synthetically prepared for biological evaluations. The biological activities of all isolated compounds were evaluated in comparison with those of 1-4 using a mouse behavioral assay upon intracerebroventricular injection, revealing key functional groups in the dopargimines and mellpaladines for in vivo behavioral toxicity. Interestingly, these alkaloids also emerged during a screen of our marine natural product library aimed at identifying antiviral activities against dengue virus, SARS-CoV-2, and vesicular stomatitis Indiana virus (VSV) pseudotyped with Ebola virus glycoprotein (VSV-ZGP).

QSAR prediction, synthesis, anticancer evaluation, and mechanistic investigations of novel sophoridine derivatives as topoisomerase I inhibitors.

Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.

Natural Distribution, Structures, Synthesis, and Bioactivity of Hasubanan Alkaloids.

Hasubanan alkaloids represent a distinct class of alkaloids bearing a structural resemblance to morphine, predominantly found in herbals of the Stephania genus. Their intriguing molecular architecture and potential analgesic properties have captured the interest of medicinal chemists worldwide. This review meticulously examines the natural distribution, structural characteristics, biosynthetic pathways, synthetic methodologies, and biological activities of hasubanans.

A Cytochrome P450 Catalyzes Oxidative Coupling Formation of Insecticidal Dimeric Indole Piperazine Alkaloids.

Cytochrome P450 (CYP450)-catalyzed oxidative coupling is an efficient strategy for using simple building blocks to construct complex structural scaffolds of natural products. Among them, heterodimeric coupling between two different monomers is relatively scarce, and the corresponding CYP450s are largely undiscovered. In this study, we discovered a fungal CYP450 (CpsD) and its associated cps cluster from 37208 CYP450s of Pfam PF00067 family member database and subsequently identified a group of new skeleton indole piperazine alkaloids (campesines A-G) by combination of genome mining and heterologous synthesis. Importantly, CYP450 CpsD mainly catalyzes intermolecular oxidative heterocoupling of two different indole piperazine monomers to generate an unexpected 6/5/6/6/6/6/5/6 eight-ring scaffold through the formation of one C-C bond and two C-N bonds, illuminating its first dimerase role in this family of natural products. The proposed catalytic mechanism of CpsD was deeply investigated by diversified substrate derivatization. Moreover, dimeric campesine G shows good insecticidal activity against the global honeybee pest Galleria mellonella. Our study shows a representative example of discovering new skeleton monomeric and dimeric indole piperazine alkaloids from microbial resources, expands our knowledge of bond formation by CYP450s and supports further development of the newly discovered and engineered campesine family compounds as potential biopesticides.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids.

Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines.

Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis.

Plants synthesize numerous alkaloids that mimic animal neurotransmitters1. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds2,3, yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids4, we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A5. Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target.

Synthesis and target annotation of the alkaloid GB18.

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans1-4. Limited, variable supply of GB alkaloids5, however, has impeded their biological exploration and clinical development6. Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally dynamic pyridine. Reliable, gram-scale access to GB18 enabled its assignment as a potent antagonist of κ- and µ-opioid receptors-the first new targets in 35 years-and lays the foundation to navigate and understand the biological activity of Galbulimima metabolites.

Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.

Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters. We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high Fsp2) followed by complete, stereoselective reduction to high fraction sp3 products (high Fsp3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.