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Nature Chemical Biology Dec 2023Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications,...
Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker's yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.
Topics: Saccharomyces cerevisiae; Monoterpenes; Indole Alkaloids; Plants; Pharmaceutical Preparations; Catharanthus; Plant Proteins
PubMed: 37932529
DOI: 10.1038/s41589-023-01430-2 -
Nature Chemical Biology Aug 2023Advances in omics technologies now permit the generation of highly contiguous genome assemblies, detection of transcripts and metabolites at the level of single cells...
Advances in omics technologies now permit the generation of highly contiguous genome assemblies, detection of transcripts and metabolites at the level of single cells and high-resolution determination of gene regulatory features. Here, using a complementary, multi-omics approach, we interrogated the monoterpene indole alkaloid (MIA) biosynthetic pathway in Catharanthus roseus, a source of leading anticancer drugs. We identified clusters of genes involved in MIA biosynthesis on the eight C. roseus chromosomes and extensive gene duplication of MIA pathway genes. Clustering was not limited to the linear genome, and through chromatin interaction data, MIA pathway genes were present within the same topologically associated domain, permitting the identification of a secologanin transporter. Single-cell RNA-sequencing revealed sequential cell-type-specific partitioning of the leaf MIA biosynthetic pathway that, when coupled with a single-cell metabolomics approach, permitted the identification of a reductase that yields the bis-indole alkaloid anhydrovinblastine. We also revealed cell-type-specific expression in the root MIA pathway.
Topics: Catharanthus; Plants, Medicinal; Multiomics; Indole Alkaloids; Antineoplastic Agents; Monoterpenes; Gene Expression Regulation, Plant; Plant Proteins
PubMed: 37188960
DOI: 10.1038/s41589-023-01327-0 -
Molecules (Basel, Switzerland) Feb 2022Two undescribed ether derivatives of sesquiterpenes, 1-ethoxycaryolane-1, 9-diol () and 2-ethoxyclovane-2, 9-diol (), and one new monoterpene glycoside,...
Two undescribed ether derivatives of sesquiterpenes, 1-ethoxycaryolane-1, 9-diol () and 2-ethoxyclovane-2, 9-diol (), and one new monoterpene glycoside, p-menthane-1,2,8-triol-4-O--D-glucoside (), were obtained, together with eight known compounds from the stems and leaves of . Their structures were elucidated by spectroscopic methods. Compounds - were evaluated for their potency against and clinical methicillin-resistant (MRSA). Among them, compound was weakly active against (MIC = 128 μg/mL), and compounds and exhibited good antibacterial activity against and MRSA (MICs = 2-8 µg/mL). A primary mechanism study revealed that compounds and could kill bacteria by destroying bacterial cell membranes. Moreover, compounds and were not susceptible to drug resistance development.
Topics: Anti-Bacterial Agents; Humans; Illicium; Methicillin-Resistant Staphylococcus aureus; Monoterpenes; Plant Leaves; Plant Stems; Sesquiterpenes; Staphylococcal Infections
PubMed: 35164380
DOI: 10.3390/molecules27031115 -
Journal of the American Chemical Society Mar 2023("kratom") is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of kratom have been linked to a complex mixture of...
("kratom") is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic center of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and fluorinated analogues.
Topics: Stereoisomerism; Secologanin Tryptamine Alkaloids; Mitragyna; Monoterpenes
PubMed: 36883326
DOI: 10.1021/jacs.2c13644 -
Biomedicine & Pharmacotherapy =... May 2022Paeoniflorin is a water-soluble monoterpenoid glycoside that can be derived from multiple herbaceous plants, such as Radix Paeoniae Rubra, Radix Paeoniae Alba, Paeonia... (Review)
Review
Paeoniflorin is a water-soluble monoterpenoid glycoside that can be derived from multiple herbaceous plants, such as Radix Paeoniae Rubra, Radix Paeoniae Alba, Paeonia suffruticosa and Cimicifugae Foetidae. Multiple studies have suggested that Paeoniflorin possesses an excellent anti-tumor effect in variety of tumors, including liver cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer and bladder cancer. It can induce cell apoptosis, inhibit proliferation, invasion and metastasis via different molecular mechanisms, which are mainly involved in nuclear transcription factor kappα (NF-κB), B-cell lymphoma-2(Bcl-2) family, MicroRNA, neural precursor cell expressed developmentally down-regulated protein 4(NEDD4) signaling pathway, transcription activating factor (STAT3), p21, p53/14-3-3 signaling pathway, transforming growth factor-β1(TGF-β1)/Smads signaling pathway, Mitogen-activated protein kinase (MAPK) signaling pathway and Notch-1. Current studies on anti-tumor effect and mechanism of action of Paeoniflorin remain unclear. Therefore, this study reviews the research progress in the anti-tumor effect and mechanism of Paeoniflorin in an attempt to provide a new thought and theoretical basis for further development and clinical application of Paeoniflorin.
Topics: Glucosides; Humans; Monoterpenes; Neoplasms; Paeonia
PubMed: 35279012
DOI: 10.1016/j.biopha.2022.112800 -
Journal of Medicinal Chemistry Apr 2023Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and...
Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives . ()-configuration in the side chain of aminodiols ( and ) led to higher σ affinity than ()-configuration ( and ). 4-Benzylpiperidines (-series) revealed higher σ affinity than 4-phenylbutylamines (-series). Aminodiol showed very high σ affinity ( = 1.2 nM), excellent selectivity over σ receptors, and promising log (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ affinity and selectivity on an atomistic level. In the capsaicin assay, exhibited similar antiallodynic activity to the prototypical σ antagonist S1RA. The antiallodynic activity of was removed by co-application of the σ agonist PRE-084, proving σ antagonism being involved in the antiallodynic effect.
Topics: Structure-Activity Relationship; Cyclohexane Monoterpenes; Receptors, sigma; Ligands; Molecular Dynamics Simulation
PubMed: 36946301
DOI: 10.1021/acs.jmedchem.2c02081 -
Communications Biology Mar 2021Monoterpenes are major constituents of plant-derived essential oils and have long been widely used for therapeutic and cosmetic applications. The monoterpenes menthol...
Monoterpenes are major constituents of plant-derived essential oils and have long been widely used for therapeutic and cosmetic applications. The monoterpenes menthol and camphor are agonists or antagonists for several TRP channels such as TRPM8, TRPV1, TRPV3 and TRPA1. However, which regions within TRPV1 and TRPV3 confer sensitivity to monoterpenes or other synthesized chemicals such as 2-APB are unclear. In this study we identified conserved arginine and glycine residues in the linker between S4 and S5 that are related to the action of these chemicals and validated these findings in molecular dynamics simulations. The involvement of these amino acids differed between TRPV3 and TRPV1 for chemical-induced and heat-evoked activation. These findings provide the basis for characterization of physiological function and biophysical properties of ion channels.
Topics: Amino Acid Sequence; Animals; Arginine; Camphor; Glycine; HEK293 Cells; Humans; Membrane Potentials; Membrane Transport Modulators; Menthol; Mice; Molecular Dynamics Simulation; Molecular Structure; Monoterpenes; Rats; Structure-Activity Relationship; Transient Receptor Potential Channels
PubMed: 33674682
DOI: 10.1038/s42003-021-01776-0 -
Molecules (Basel, Switzerland) Jun 2020Epicatechocorynantheines A and B, and epicatechocorynantheidine were isolated from the stem bark of . These molecules were pinpointed, and their isolation streamlined,...
Epicatechocorynantheines A and B, and epicatechocorynantheidine were isolated from the stem bark of . These molecules were pinpointed, and their isolation streamlined, by a molecular networking strategy. The structural elucidation was unambiguously accomplished from HRMS and 1D/2D NMR data. These compounds represent the first examples of corynanthean-type alkaloids tethered with a flavonoid. Epicatechocorynantheidine notably instigated two connections between the monoterpene indole alkaloid and the flavonoid, yielding an unprecedented octacyclic appendage. These flavoalkaloids exerted moderate antiplasmodial activities.
Topics: Anthelmintics; Catechin; Flavonoids; Indole Alkaloids; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Monoterpenes; Pausinystalia; Plant Bark; Plant Stems
PubMed: 32517373
DOI: 10.3390/molecules25112654 -
Molecules (Basel, Switzerland) May 2024Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of... (Review)
Review
Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of plant-based medicine has been gaining interest from several researchers. Carvacrol and its isomeric compound, thymol, are plant-based extracts that possess several biological activities, such as antimalarial, anticancer, antifungal, and antibacterial. However, their efficacy is compromised by their poor bioavailability. Thus, medicinal scientists have explored the synthesis of hybrid compounds containing their pharmacophores to enhance their therapeutic efficacy and improve their bioavailability. Hence, this review is a comprehensive report on hybrid compounds containing carvacrol and its isomer, thymol, with potent anticancer and antibacterial agents reported between 2020 and 2024. Furthermore, their structural activity relationship (SAR) and recommended future strategies to further enhance their therapeutic effects will be discussed.
Topics: Thymol; Cymenes; Humans; Anti-Bacterial Agents; Antineoplastic Agents; Structure-Activity Relationship; Neoplasms; Animals
PubMed: 38792138
DOI: 10.3390/molecules29102277 -
Molecules (Basel, Switzerland) Oct 2022For the first time, monoterpene trifluoromethylated β-hydroxy-benzyl--oximes were synthesized in 81-95% yields by nucleophilic addition of the Ruppert-Prakash reagent...
For the first time, monoterpene trifluoromethylated β-hydroxy-benzyl--oximes were synthesized in 81-95% yields by nucleophilic addition of the Ruppert-Prakash reagent (TMSCF) to the corresponding β-keto-benzyl--oximes based on (+)-nopinone, (-)-verbanone and (+)-camphoroquinone. Trifluoromethylation has been determined to entirely proceed chemo- and stereoselective at the C=O rather than C=N bond. Trifluoromethylated benzyl--oximes were reduced to the corresponding α-trifluoromethyl-β-amino alcohols in 82-88% yields. The structure and configuration of the compounds obtained have been established.
Topics: Amino Alcohols; Molecular Structure; Monoterpenes; Indicators and Reagents; Oximes
PubMed: 36296661
DOI: 10.3390/molecules27207068