RESUMO
Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor-dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.
Assuntos
Ferro , Macrófagos , Monoterpenos , Tropolona/análogos & derivados , Animais , Proteínas de Transporte de Cátions/deficiência , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Macrófagos/metabolismo , Camundongos , Monoterpenos/metabolismo , Transferrina/metabolismo , Tropolona/metabolismo , Peixe-Zebra/metabolismoRESUMO
Pseudomonas donghuensis P482 exhibits broad antimicrobial activity against phytopathogens, including the soft rot bacteria of the Dickeya genus. Here, we report that under limited nutrient availability, the antibacterial activity of P. donghuensis P482 against Dickeya solani requires the reciprocal action of two iron scavengers: 7-hydroxytropolone (7-HT) and a newly characterized pyoverdine (PVDP482 ) and is quenched in the iron-augmented environment. Further, we show that the biosynthesis of pyoverdine and 7-HT is metabolically coordinated, and the functional BV82_4709 gene involved in 7-HT synthesis is pivotal for expressing the BV82_3755 gene, essential for pyoverdine biosynthesis and vice versa. The synthesis of both scavengers is under the control of Gac/Rsm, but only PVD is controlled by Fur. The isoelectric focusing profile of the P482 siderophore differs from that of the other Pseudomonas spp. tested. This finding led to the unveiling of the chemical structure of the new pyoverdine PVDP482 . To summarize, the antibacterial activity of P. donghuensis P482 is attributed to 7-HT and PVDP482 varies depending on the nutrient and iron availability, highlighting the importance of these factors in the competition between P482 and D. solani.
Assuntos
Ferro , Oligopeptídeos , Pseudomonas , Tropolona/análogos & derivados , Pseudomonas/genética , Sideróforos/genética , Antibacterianos/farmacologia , Pseudomonas aeruginosa/genéticaRESUMO
Eupenifeldin (1) is a fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A series of ester (2-6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-30) analogues of 1 were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained. The cytotoxic activities of 1-30 were evaluated against human melanoma and ovarian cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of 1 (i.e., 2-8) maintained cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue (6), which was acylated on the secondary hydroxy at the 11 position.
Assuntos
Antineoplásicos , Tropolona , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Fungos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Tropolona/química , Tropolona/farmacologia , Tropolona/análogos & derivados , Tropolona/síntese química , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , Sulfonatos de Arila/farmacologiaRESUMO
BACKGROUND AND OBJECTIVE: Efferocytosis is a process whereby macrophages remove apoptotic cells, such as neutrophils, that have accumulated in tissues, which is required for resolution of inflammation. Efferocytosis is impaired in individuals with increasing age and in those with various systemic diseases. Recently, efferocytosis has been reported to be related to the pathogenesis and progression of periodontitis, and enhancement of efferocytosis, especially in the subjects with impaired efferocytosis, was suggested to lead to periodontitis prevention and care. Various anti-inflammatory ingredients are used in oral care products, but their effect on efferocytosis is unclear. Here, we aimed to identify ingredients contained in oral care products that are effective for efferocytosis regulation. METHODS: The ability of dead cells to induce inflammation in human gingival fibroblast (HGF) cells were evaluated by measuring IL-6 secretion. Six ingredients in oral care products used as anti-inflammatory agents were evaluated for their effect on efferocytosis using flow cytometry. The expression of various efferocytosis-related molecules, such as MERTK and LRP1 involved in recognition, and LXRα and ABCA1 that function in metabolism, were measured in RAW264.7 cells with or without ingredient treatment. Rac1 activity, which is related to the uptake of dead cells, was measured using the G-LISA kit. RESULTS: Dead cells elicited IL-6 secretion in HGF cells. Among the six ingredients, GK2 and hinokitiol enhanced efferocytosis activity. GK2 and hinokitiol significantly increased the expression of MERTK and LRP1, and also enhanced LXRα and ABCA1 expression after efferocytosis. Furthermore, they increased Rac1 activity in the presence of dead cells. CONCLUSION: Among the six ingredients tested, GK2 and hinokitiol promoted efferocytosis by regulating apoptotic cell recognition, uptake, and metabolism-related molecules. Efferocytosis upregulation may be one of the mechanisms of GK2 and hinokitiol in the treatment of inflammatory diseases, such as periodontitis.
Assuntos
Apoptose , Gengiva , Ácido Glicirrízico , Macrófagos , Monoterpenos , Fagocitose , Tropolona , Apoptose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Humanos , Tropolona/análogos & derivados , Tropolona/farmacologia , Fagocitose/efeitos dos fármacos , Gengiva/citologia , Gengiva/metabolismo , Gengiva/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Monoterpenos/farmacologia , Camundongos , Animais , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Interleucina-6/metabolismo , Células Cultivadas , EferocitoseRESUMO
In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.
Assuntos
Croton , Sesquiterpenos , Tropolona/análogos & derivados , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Ciclo-Oxigenase 2/metabolismo , Sesquiterpenos/farmacologia , Lipopolissacarídeos/farmacologiaRESUMO
Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO-OH-Nap is an α-substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO-OH-Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co-incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO-OH-Nap-treated OS cells. MO-OH-Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron-regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO-OH-Nap on iron-homeostasis pathways in OS cells. Furthermore, MO-OH-Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO-OH-Nap-treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO-OH-Nap-induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO-OH-Nap as a novel treatment for OS.
Assuntos
Osteossarcoma , Tropolona , Humanos , Tropolona/farmacologia , Ferro/metabolismo , Ferro/farmacologia , Apoptose , Linhagem Celular , Osteossarcoma/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (ß-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.
Assuntos
Neoplasias da Mama , Monoterpenos , Tropolona , Tropolona/análogos & derivados , Humanos , Feminino , Tropolona/farmacologia , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia , Apoptose , Autofagia , Células MCF-7 , Receptores de Hialuronatos , Fatores de Transcrição SOXB1RESUMO
Utilizing Density Functional Theory (DFT) calculations at the B3LYP/QZVP level and incorporating the Conductor-like Polarizable Continuum Model (C-PCM) for solvation, the thermodynamic and chemical activity properties of 21-(hydroxymethoxy)henicosadecaenal, identified in cultured freshwater pearls from the mollusk Hyriopsis cumingii, have been elucidated. The study demonstrates that this compound releases formaldehyde, a potent antimicrobial agent, through dehydrogenation and deprotonation processes in both hydrophilic and lipophilic environments. Moreover, this polyenal exhibits strong anti-reductant properties, effectively scavenging free radicals. These critical properties classify the pearl-derived ingredient as a natural multi-functional compound, serving as a coloring, antiradical, and antimicrobial agent. The 2-(hydroxymethoxy)vinyl (HMV) moiety responsible for the formaldehyde release can be transferred to other compounds, thereby enhancing their biological activity. For instance, tyrosol (4-(2-hydroxyethyl)phenol) can be modified by substituting the less active 2-hydroxyethyl group with the active HMV one, and hinokitiol (4-isopropylotropolone) can be functionalized by attaching this moiety to the tropolone ring. A new type of meso-carrier, structurally modeled on pearls, with active substances loaded both in the layers and the mineral part, has been proposed.
Assuntos
Álcool Feniletílico , Tropolona , Tropolona/análogos & derivados , Tropolona/química , Tropolona/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Monoterpenos/química , Monoterpenos/farmacologia , Formaldeído/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Estrutura Molecular , TermodinâmicaRESUMO
Tropolone is a non-benzenoid aromatic scaffold with unique photophysical and metal-chelating properties. Recently, it has been conjugated with DNA, and the photophysical properties of this conjugate have been explored. Tropolonyl-deoxyuridine (tr-dU) is a synthetic fluorescent DNA nucleoside analogue that exhibits pH-dependent emissions. However, its solvent-dependent fluorescence properties are unexplored owing to its poor solubility in most organic solvents. It would be interesting to incorporate it into DNA primer enzymatically. This report describes the solvent-dependent fluorescence properties of the silyl-derivative, and enzymatic incorporation of its triphosphate analogue. For practical use, its cell-internalization and cytotoxicity are also explored. tr-dU nucleoside was found to be a potential analogue to design DNA probes and can be explored for various therapeutic applications in the future.
Assuntos
DNA , Tropolona , Humanos , Tropolona/farmacologia , Células HeLa , DNA/metabolismo , Nucleosídeos , Timidina , Corantes Fluorescentes , SolventesRESUMO
A bacterial strain, Pseudomonas bohemica strain ins3 was newly isolated as a resistant strain against high concentrations of hinokitiol. This strain was revealed not only to show resistance but also completely remove this compound from its culture broth. In addition, its mechanism was revealed to be independent of conventional aromatic dioxygenases, ie catechol-1,2- or 2,3-dioxygenases.
Assuntos
Antibacterianos , Dioxigenases , Monoterpenos , Pseudomonas , TropolonaRESUMO
We present the preparation of a series of novel natural product-like homobarrelenones, norcaranes, and dihydrofluorenones through a diversity-oriented synthetic (DOS) strategy that combines Diels-Alder reactions and phototransformations, as well as their biological evaluation against MCF-7, HT-29, and NCI-H460 human tumor cells. Six of these demonstrated activities in the micromolar range against the three cell lines, and none were predicted as cytotoxic against human nontumor cells according to in silico studies. In addition, within the set of active derivatives, three exhibited low unspecific cytotoxicity in a sperm motility assay. The rich functionality of the new compounds makes them ideal candidates for exhaustive structure-activity relationship studies.
Assuntos
Antineoplásicos , Biflavonoides , Masculino , Humanos , Relação Estrutura-Atividade , Tropolona/farmacologia , Motilidade dos Espermatozoides , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Estrutura Molecular , Proliferação de CélulasRESUMO
A paper titled "On the Synthesis of Hinokitiol" appeared in this journal in 1950 and marked the beginning of a new research field of novel aromatics.
Assuntos
Monoterpenos , TropolonaRESUMO
The synthesis of functionalized aromatic compounds is a central theme of research for modern organic chemistry. Despite the increasing finesse in the functionalization of five- and six-membered aromatic rings, their seven-membered-ring sibling, tropolone (2-hydroxy-2,4,6-cycloheptatrien-1-one), remains a challenging target for synthetic derivatization. This challenge primarily emanates from the unique structural and chemical properties of tropolonoid compounds, which often lead to unexpected and undesired reaction outcomes under conditions developed for the functionalizations of other aromatic moieties. Herein, we describe the total synthesis of one of the most complex natural tropolonoids, gukulenin B. Our synthetic route features a series of site-selective aromatic C-H bond functionalizations and C-C bond formations, whose reaction conditions are judiciously tuned to allow uncompromised performance on the tropolone nucleus. The flexibility and modularity of our synthesis are expected to facilitate further synthetic and biological studies of the gukulenin family of cytotoxins. In addition, the methods and tactics developed herein for the functionalization of the tropolone moiety could inspire and enable chemists of multiple disciplines to take advantage of this privileged yet underexplored structural motif.
Assuntos
Terpenos , Tropolona , Compostos OrgânicosRESUMO
The α-hydroxytropolones (αHTs) are troponoid inhibitors of hepatitis B virus (HBV) replication that can target HBV RNase H with submicromolar efficacies. αHTs and related troponoids (tropones and tropolones) can be cytotoxic in cell lines as measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays that assess mitochondrial function. Previous studies suggest that tropolones induce cytotoxicity through inhibition of mitochondrial respiration. Therefore, we screened 35 diverse troponoids for effects on mitochondrial function, mitochondrial/nuclear genome ratios, cytotoxicity, and reactive oxygen species (ROS) production. Troponoids as a class did not inhibit respiration or glycolysis, although the α-ketotropolone subclass interfered with these processes. The troponoids had no impact on the mitochondrial DNA/nuclear DNA ratio after 3 days of compound exposure. The patterns of troponoid-induced cytotoxicity among three hepatic cell lines were similar for all compounds, but three potent HBV RNase H inhibitors were not cytotoxic in primary human hepatocytes. Tropolones and αHTs increased ROS production in cells at cytotoxic concentrations but had no effect at lower concentrations that efficiently inhibit HBV replication. Troponoid-mediated cytotoxicity was significantly decreased upon the addition of the ROS scavenger N-acetylcysteine. These studies show that troponoids can increase ROS production at high concentrations within cell lines, leading to cytotoxicity, but are not cytotoxic in primary hepatocytes. Future development of αHTs as potential therapeutics against HBV may need to mitigate ROS production by altering compound design and/or by coadministering ROS antagonists to ameliorate increased ROS levels.
Assuntos
Vírus da Hepatite B , Replicação Viral , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio , Ribonuclease H/genética , Tropolona/farmacologiaRESUMO
BACKGROUND: Resistance to radiotherapy is a common cause of treatment failure in advanced head and neck squamous cell carcinoma (HNSCC). ß-Thujaplicin, a natural tropolone derivative, acts as an anti-cancer agent and has recently been shown to radiosensitize non-HNSCC cancer cells. However, no data is currently available on its radiosensitizing potential in HNSCC. METHODS: To investigate the effect of ß-Thujaplicin and irradiation in HNSCC cell lines CAL27 and FADU, we performed a cell viability assay, colony forming assay, flow cytometry for cell cycle analysis and a wound healing assay. Drug-irradiation interaction was analyzed using a zero-interaction potency model. RESULTS: Treatment with ß-Thujaplicin led to a dose-dependent decrease in cell viability and enhanced the effect of irradiation. Clonogenic survival was inhibited with synergistic drug-irradiation interaction. ß-Thujaplicin further led to S-phase arrest and increased the sub-G1 population. Moreover, combined ß-Thujaplicin and irradiation treatment had a higher anti-migratory effect compared to irradiation alone. CONCLUSIONS: ß-Thujaplicin acts as a radiosensitizer in HNSCC cell lines. Further evaluation of its use in HNSCC therapy is warranted.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Radiossensibilizantes , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Monoterpenos , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Tropolona/análogos & derivados , Tropolona/farmacologiaRESUMO
Polyoxygenated tropolones possess a broad range of biological activity, and as a result are promising lead structures or fragments for drug development. However, structure-function studies and subsequent optimization have been challenging, in part due to the limited number of readily available tropolones and the obstacles to their synthesis. Oxidopyrylium [5+2] cycloaddition can effectively generate a diverse array of seven-membered ring carbocycles, and as a result can provide a highly general strategy for tropolone synthesis. Here, we describe the use of 3-hydroxy-4-pyrone-based oxidopyrylium cycloaddition chemistry in the synthesis of functionalized 3,7-dimethoxytropolones, 3,7-dihydroxytropolones, and isomeric 3-hydroxy-7-methoxytropolones through complementary benzyl alcohol-incorporating procedures. The antiviral activity of these molecules against herpes simplex virus-1 and hepatitis B virus is also described, highlighting the value of this approach and providing new structure-function insights relevant to their antiviral activity.
Assuntos
Herpesvirus Humano 1 , Tropolona , Antivirais/farmacologia , Reação de Cicloadição , Vírus da Hepatite B , Tropolona/química , Tropolona/farmacologiaRESUMO
Herein, we describe the formation of tropolones through the autoxidation of Büchner reaction-derived cycloheptatrienes. The reaction is exceptionally simple procedurally, as it involves blowing a stream of compressed air over the cycloheptatriene, and the products can be obtained without any need for chromatography. The chemistry works specifically on dioxolane-fused systems or close variants, and substitution patterns are also important. A radical-based mechanistic hypothesis is put forward to explain these results. Finally, we demonstrate the utility of the overall process in the synthesis of amide-appended tropolones and an isomer of stipitatic acid.
Assuntos
Dioxóis , Tropolona , Tropolona/químicaRESUMO
A series of tropone-fused porphyrinoids with unique spectroscopic features has been prepared. A dimethyl tropone-fused pyrrole was reacted with lead tetraacetate to give a bis(acetoxymethyl) derivative that condensed with an α-unsubstituted pyrrole tert-butyl ester to form a tripyrrane intermediate. Cleavage of the tert-butyl ester protective groups, followed by condensation with a series of aromatic dialdehydes and oxidation with DDQ, afforded the tropone-fused porphyrinoid systems. Reactions with pyrrole, furan, thiophene, and selenophene dialdehydes gave tropone-fused porphyrins and related heteroporphyrins. In addition, indene, 4-hydroxybenzene, and 3-hydroxypyridine dicarbaldehydes generated examples of carba-, oxybenzi-, and oxypyriporphyrins. The electronic absorption spectra of the tropone-fused porphyrinoids were greatly altered, showing shifts to longer wavelengths and the appearance of strong Q bands between 600 and 800 nm. The proton nuclear magnetic resonance spectra were also very unusual, as the internal protons were strongly shifted upfield, in some cases giving rise to resonances that approached -10 ppm. However, the external protons showed reduced downfield shifts compared to porphyrinoids that do not have tropone ring fusion. The profound changes observed for these macrocycles demonstrate that the introduction of fused tropone units, together with other structural changes such as core modification, can provide the means by which porphyrinoids with unique spectroscopic properties can be accessed.
Assuntos
Porfirinas , Oxirredução , Pirróis , Tropolona/análogos & derivadosRESUMO
The influence of base type, temperature, and solvent on regioselective C(9)/C(10) "click" modifications within the tropolone ring of colchiceine (2) is investigated. New ether derivatives of 2, bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine (1) or colchiceine (2), ether congeners, as e.g. 3e [IC50s(3e) â¼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (IC50s â¼ 1-2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of αGTP/ß tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.
Assuntos
Antineoplásicos/farmacologia , Colchicina/farmacologia , Compostos Heterocíclicos/farmacologia , Tropolona/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tropolona/síntese química , Tropolona/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
In order to explore novel natural product-based anti-oomycete and nematicidal agents, sixteen unreported 2-sulfonyloxyhinokitiol derivatives were prepared using the principle of active splicing, and structurally confirmed by proton nuclear magnetic resonance (1 H-NMR), carbon-13 nuclear magnetic resonance (13 C-NMR), high-resolution mass spectrometry (HRMS), and melting point. Moreover, we evaluated the title compounds as anti-oomycete and nematicidal agents against two serious agricultural pests of Phytophthora capsici and Meloidogyne incongnita. Among the sixteen hinokitiol esters tested: (1) Compounds 3a and 3m exhibited the most potent anti-oomycete activity compared to zoxamide against P. capsici, and the median effective concentration (EC50 ) values of 3a, 3m, and zoxamide were 18.64, 21.11, and 23.15â mg/L, respectively; Further studies showed that the existence of seven membered ring and carbonyl group was the necessary condition for the high anti-oomycete activity of hinokitiol. (2) Compounds 3n and 3p exhibited more promising nematicidal activity than hinokitiol, and the median lethal concentration (LC50 ) values of 3n, 3p and 1 against M. incongnita were 0.2111, 0.2079, and 0.3933â mg/L, respectively. This result will pave the way for further modification of hinokitiol to develop potential new fungicides and nematicides.