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Natural Product Research May 2024This study employed the MTT assay to assess the cytotoxicity of one flavan and two stilbene derivatives isolated from the false indigo-bush ( L.) fruits:...
This study employed the MTT assay to assess the cytotoxicity of one flavan and two stilbene derivatives isolated from the false indigo-bush ( L.) fruits: 5,7-dihydroxy-8-geranylflavanone (), 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (), and 2-carboxy-3-hydroxy-4-prenyl-5-methoxybibenzyl (). The examined compounds reduced the survival of human cervical and colon tumour cells (HeLa, HT-29, HCT-116, and LS174) with IC values ranging from 10.55 to 147.09 μg/mL, except for , which did not affect LS174 cells within the tested concentrations. The highest activity was observed for against HeLa cells, and also exhibited the weakest effect against normal foetal lung fibroblasts (IC = 166.11 μg/mL), demonstrating good potency and selectivity. Stilbenes and proved efficacious, but lacked selectivity compared to . Our findings revealed the cytotoxicity of false indigo-bush constituents, justifying further mechanistic and investigations, particularly on 5,7-dihydroxy-8-geranylflavanone, which displayed considerable anticancer capacity and a potentially favourable safety profile.
PubMed: 38733625
DOI: 10.1080/14786419.2024.2353912 -
Prenylated Flavonoids of the Moraceae Family: A Comprehensive Review of Their Biological Activities.Plants (Basel, Switzerland) Apr 2024Prenylated flavonoids (PFs) are natural flavonoids with a prenylated side chain attached to the flavonoid skeleton. They have great potential for biological activities... (Review)
Review
Prenylated flavonoids (PFs) are natural flavonoids with a prenylated side chain attached to the flavonoid skeleton. They have great potential for biological activities such as anti-diabetic, anti-cancer, antimicrobial, antioxidant, anti-inflammatory, enzyme inhibition, and anti-Alzheimer's effects. Medicinal chemists have recently paid increasing attention to PFs, which have become vital for developing new therapeutic agents. PFs have quickly developed through isolation and semi- or full synthesis, proving their high value in medicinal chemistry research. This review comprehensively summarizes the research progress of PFs, including natural PFs from the Moraceae family and their pharmacological activities. This information provides a basis for the selective design and optimization of multifunctional PF derivatives to treat multifactorial diseases.
PubMed: 38732426
DOI: 10.3390/plants13091211 -
Molecules (Basel, Switzerland) Apr 2024Terpenoid alkaloids are recognized as a class of compounds with limited numbers but potent biological activities, primarily derived from plants, with a minor proportion... (Review)
Review
Terpenoid alkaloids are recognized as a class of compounds with limited numbers but potent biological activities, primarily derived from plants, with a minor proportion originating from animals and microorganisms. These alkaloids are synthesized from the same prenyl unit that forms the terpene skeleton, with the nitrogen atom introduced through β-aminoethanol, ethylamine, or methylamine, leading to a range of complex and diverse structures. Based on their skeleton type, they can be categorized into monoterpenes, sesquiterpenes, diterpenes, and triterpene alkaloids. To date, 289 natural terpenoid alkaloids, excluding triterpene alkaloids, have been identified in studies published between 2019 and 2024. These compounds demonstrate a spectrum of biological activities, including anti-inflammatory, antitumor, antibacterial, analgesic, and cardioprotective effects, making them promising candidates for further development. This review provides an overview of the sources, chemical structures, and biological activities of natural terpenoid alkaloids, serving as a reference for future research and applications in this area.
Topics: Alkaloids; Terpenes; Humans; Animals; Anti-Inflammatory Agents; Molecular Structure
PubMed: 38731459
DOI: 10.3390/molecules29091968 -
American Journal of Physiology.... Jul 2024Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only...
Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the posttranslational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein, we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphological response to chemoattractant C5a. The immunomodulatory effect of prenylation is ill-defined. We investigated the role of prenylation on the chemoattractant response to C5a. Simvastatin treatment inhibits the cytoskeletal remodeling associated with a chemotactic response. We showed that the chemoattractant response to C5a was dependent on geranylgeranylation, and proteomic analysis identified several geranylgeranylated proteins that are involved in C5a receptor signaling and cytoskeletal remodeling. Furthermore, they establish the role of geranylgeranylation in mediating the response to chemoattractant C5a.
Topics: Polyisoprenyl Phosphates; Humans; Simvastatin; Chemotactic Factors; Phagocytes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Complement C5a; Protein Prenylation; Animals; Mice; Sesquiterpenes
PubMed: 38717364
DOI: 10.1152/ajpendo.00359.2023 -
Beilstein Journal of Organic Chemistry 2024Terpenoids are one of the largest class of natural products with diverse structures and activities. This enormous diversity is embedded in enzymes called terpene... (Review)
Review
Terpenoids are one of the largest class of natural products with diverse structures and activities. This enormous diversity is embedded in enzymes called terpene synthases (TSs), which generate diverse terpene skeletons via sophisticated cyclization cascades. In addition to the many highly selective TSs, there are many promiscuous TSs that accept multiple prenyl substrates, or even noncanonical ones, with 6, 7, 8, 11, and 16 carbon atoms, synthesized via chemical approaches, -methyltransferases, or engineered lepidopteran mevalonate pathways. The substrate promiscuity of TSs not only expands the structural diversity of terpenes but also highlights their potential for the discovery of novel terpenoids via combinatorial biosynthesis. In this review, we focus on the current knowledge on multisubstrate terpene synthases (MSTSs) and highlight their potential applications.
PubMed: 38711588
DOI: 10.3762/bjoc.20.86 -
Phytochemistry Jul 2024Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus...
Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC value of 17.9-29.7 μM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.
Topics: Talaromyces; Diketopiperazines; Humans; Molecular Structure; Prenylation; Drug Screening Assays, Antitumor; Structure-Activity Relationship; Antineoplastic Agents; Indole Alkaloids; Alkaloids; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hep G2 Cells; Cell Proliferation; Phosphoric Monoester Hydrolases; Cell Line, Tumor
PubMed: 38705266
DOI: 10.1016/j.phytochem.2024.114119 -
Chemistry (Weinheim An Der Bergstrasse,... May 20242,5-Dimethyl-2,4-hexadiene is a readily available and easily managable compound, whose symmetric and polymethylated dienic structure should be prone to engage in...
2,5-Dimethyl-2,4-hexadiene is a readily available and easily managable compound, whose symmetric and polymethylated dienic structure should be prone to engage in cross-metathesis reactions with other alkenes, but this has not been apparently exploited so far. Here we show that this reactant enables the easy synthesis of tri- and tetra-susbtituted alkenes (i. e. isobutylenyl and prenyl groups) from simple alkenes under mild reaction conditions, not only with the conventional 2 generation Grubbs catalyst but also with other Grela-type catalyts such as StickyCat, AquaMet and GreenCat. The use of liquid and low volatile 2,5-dimethyl-2,4-hexadiene avoids the use of gaseous alkene reactants and, besides, showcases the reactivity of polyisoprene (rubber), thus allowing to optimize the reaction conditions for rubber upcycling, after metathesis reaction of the pristine or used polymer with simple alkenes. These results bring low volatile isoprene-type compounds as privileged poly-substituted reactants for alkene cross-metathesis reactions.
PubMed: 38699858
DOI: 10.1002/chem.202400860 -
Bioorganic & Medicinal Chemistry Letters Jul 2024We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have...
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Topics: Metabolic Syndrome; Quinolines; Structure-Activity Relationship; Humans; Peroxisome Proliferator-Activated Receptors; Molecular Structure; Lipopolysaccharides; Anti-Inflammatory Agents; Macrophages; Dose-Response Relationship, Drug; Benzopyrans; Animals; Mice
PubMed: 38677560
DOI: 10.1016/j.bmcl.2024.129770 -
Molecules (Basel, Switzerland) Apr 2024L. is widely distributed in tropical regions and the ethnobotanical uses of this species encompass medicinal applications for the treatment of respiratory,...
L. is widely distributed in tropical regions and the ethnobotanical uses of this species encompass medicinal applications for the treatment of respiratory, antimicrobial, and gynecological diseases. Chemical studies reveal a diverse array of secondary metabolites, including terpenes, flavonoids, and prenylated compounds. Extracts from have shown antibacterial, antifungal, and larvicidal activities. Our study explores the activity of extracts and partitions against H37Rv, as well as the chemical diversity of the bioactive partition. This marks the first investigation of the bioactive partition of from agroecological cultivation. The ethyl acetate partition from the ethanolic leaf extract (PAEPL) was found to be the most active. PAEPL was subjected to column chromatography using Sephadex LH-20 and the obtained fractions were analyzed using UHPLC-HRMS/MS. The MS/MS data from the fractions were submitted to the online GNPS platform for the generation of the molecular network, which displayed 1714 nodes and 167 clusters. Compounds were identified via manual inspection and different libraries, allowing the annotation of 83 compounds, including flavonoids, benzoic acid derivatives, glycosides, free fatty acids, and glycerol-esterified fatty acids. This study provides the first chemical fingerprint of an antimycobacterial sample from cultivated in an agroecological system.
Topics: Piper; Chromatography, High Pressure Liquid; Plant Extracts; Tandem Mass Spectrometry; Mycobacterium tuberculosis; Plant Leaves; Flavonoids; Microbial Sensitivity Tests
PubMed: 38675510
DOI: 10.3390/molecules29081690 -
Pharmaceutics Apr 2024Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into... (Review)
Review
Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into clinical trials. Resveratrol, despite its well-reported therapeutic benefits, is not metabolically stable and thus has not been utilized as an effective clinical drug. This is because it needs to be consumed in large amounts to overcome the burdens of bioavailability and conversion into less effective metabolites. Herein, we summarize the more relevant approaches to modify resveratrol, aiming to increase its biological and therapeutic efficacy. We discuss combination therapies, derivatization, and the use of resveratrol nanoparticles. Interestingly, the combination of resveratrol with established chemotherapeutic drugs has shown promising therapeutic effects on colon cancer (with oxaliplatin), liver cancer (with cisplatin, 5-FU), and gastric cancer (with doxorubicin). On the other hand, derivatizing resveratrol, including hydroxylation, amination, amidation, imidation, methoxylation, prenylation, halogenation, glycosylation, and oligomerization, differentially modifies its bioavailability and could be used for preferential therapeutic outcomes. Moreover, the encapsulation of resveratrol allows its trapping within different forms of shells for targeted therapy. Depending on the nanoparticle used, it can enhance its solubility and absorption, increasing its bioavailability and efficacy. These include polymers, metals, solid lipids, and other nanoparticles that have shown promising preclinical results, adding more "hype" to the research on resveratrol. This review provides a platform to compare the different approaches to allow directed research into better treatment options with resveratrol.
PubMed: 38675230
DOI: 10.3390/pharmaceutics16040569