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1.
Nat Commun ; 12(1): 1431, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664266

RESUMO

The structural complexity and bioactivity of natural products often depend on enzymatic redox tailoring steps. This is exemplified by the generation of the bisbenzannulated [5,6]-spiroketal pharmacophore in the bacterial rubromycin family of aromatic polyketides, which exhibit a wide array of bioactivities such as the inhibition of HIV reverse transcriptase or DNA helicase. Here we elucidate the complex flavoenzyme-driven formation of the rubromycin pharmacophore that is markedly distinct from conventional (bio)synthetic strategies for spiroketal formation. Accordingly, a polycyclic aromatic precursor undergoes extensive enzymatic oxidative rearrangement catalyzed by two flavoprotein monooxygenases and a flavoprotein oxidase that ultimately results in a drastic distortion of the carbon skeleton. The one-pot in vitro reconstitution of the key enzymatic steps as well as the comprehensive characterization of reactive intermediates allow to unravel the intricate underlying reactions, during which four carbon-carbon bonds are broken and two CO2 become eliminated. This work provides detailed insight into perplexing redox tailoring enzymology that sets the stage for the (chemo)enzymatic production and bioengineering of bioactive spiroketal-containing polyketides.


Assuntos
Antibacterianos/síntese química , Furanos/síntese química , Oxigenases de Função Mista/metabolismo , Policetídeos/química , Compostos de Espiro/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , DNA Helicases/antagonistas & inibidores , Furanos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Oxirredução , Policetídeos/farmacologia , Compostos de Espiro/farmacologia
2.
Nat Chem ; 13(1): 47-55, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33353970

RESUMO

Polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many polyether ionophores possess potent antimicrobial activity and a few selected compounds have the ability to target aggressive cancer cells. Nevertheless, ionophore function is believed to be associated with idiosyncratic cellular toxicity and, consequently, human clinical development has not been pursued. Here, we demonstrate that structurally novel polyether ionophores can be efficiently constructed by recycling components of highly abundant polyethers to afford analogues with enhanced antibacterial selectivity compared to a panel of natural polyether ionophores. We used classic degradation reactions of the natural polyethers lasalocid and monensin and combined the resulting fragments with building blocks provided by total synthesis, including halogen-functionalized tetronic acids as cation-binding groups. Our results suggest that structural optimization of polyether ionophores is possible and that this area represents a potential opportunity for future methodological innovation.


Assuntos
Antibacterianos/síntese química , Éteres/química , Ionóforos/química , Aldeídos/química , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Furanos/síntese química , Furanos/química , Humanos , Ionóforos/síntese química , Ionóforos/farmacologia , Lasalocida/síntese química , Lasalocida/química , Conformação Molecular , Monensin/síntese química , Monensin/química , Oxirredução
3.
Nucleic Acids Res ; 48(14): 7653-7664, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32667657

RESUMO

Small molecule-based modulation of a triple helix in the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been proposed as an attractive avenue for cancer treatment and a model system for understanding small molecule:RNA recognition. To elucidate fundamental recognition principles and structure-function relationships, we designed and synthesized nine novel analogs of a diphenylfuran-based small molecule DPFp8, a previously identified lead binder of MALAT1. We investigated the role of recognition modalities in binding and in silico studies along with the relationship between affinity, stability and in vitro enzymatic degradation of the triple helix. Specifically, molecular docking studies identified patterns driving affinity and selectivity, including limited ligand flexibility, as observed by ligand preorganization and 3D shape complementarity for the binding pocket. The use of differential scanning fluorimetry allowed rapid evaluation of ligand-induced thermal stabilization of the triple helix, which correlated with decreased in vitro degradation of this structure by the RNase R exonuclease. The magnitude of stabilization was related to binding mode and selectivity between the triple helix and its precursor stem loop structure. Together, this work demonstrates the value of scaffold-based libraries in revealing recognition principles and of raising broadly applicable strategies, including functional assays, for small molecule-RNA targeting.


Assuntos
Furanos/química , RNA Longo não Codificante/química , Exorribonucleases/metabolismo , Furanos/síntese química , Ligantes , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Estabilidade de RNA , RNA Longo não Codificante/metabolismo
4.
J Med Chem ; 63(9): 4867-4879, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32348139

RESUMO

We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2' ligands. These inhibitors were designed to enhance the ligand-backbone binding and van der Waals interactions in the protease active site. A number of inhibitors containing the new P2 ligand, an aminobenzothiazole as the P2' ligand and a difluorophenylmethyl as the P1 ligand, displayed very potent enzyme inhibitory potency and also showed excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been synthesized efficiently in an optically active form using enzymatic desymmetrization of meso-1,2-(dihydroxymethyl)cyclohex-4-ene as the key step. We determined high-resolution X-ray structures of inhibitor-bound HIV-1 protease. These structures revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insights into the binding properties of these new inhibitors.


Assuntos
Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Substituição de Aminoácidos , Domínio Catalítico , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Furanos/síntese química , Furanos/metabolismo , Protease de HIV/química , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/metabolismo , HIV-1/enzimologia , Compostos Heterocíclicos de Anel em Ponte/síntese química , Compostos Heterocíclicos de Anel em Ponte/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ligação Proteica , Estereoisomerismo
5.
Chemistry ; 26(24): 5441-5448, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32271495

RESUMO

N6 -(2-Deoxy-α,ß-d-erythropentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy⋅dG) is a major DNA lesion produced from 2'-deoxyguanosine under oxidizing conditions. Fapy⋅dG is produced from a common intermediate that leads to 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OxodGuo), and in greater quantities in cells. The impact of Fapy⋅dG on DNA structure and function is much less well understood than that of 8-OxodGuo. This is largely due to the significantly greater difficulty in synthesizing oligonucleotides containing Fapy⋅dG than 8-OxodGuo. We describe a synthetic approach for preparing oligonucleotides containing Fapy⋅dG that will facilitate intensive studies of this lesion in DNA. A variety of oligonucleotides as long as 30 nucleotides are synthesized. We anticipate that the chemistry described herein will provide an impetus for a wide range of studies involving Fapy⋅dG.


Assuntos
8-Hidroxi-2'-Desoxiguanosina/síntese química , DNA/química , Desoxiguanosina/química , Formamidas/síntese química , Furanos/síntese química , Oligonucleotídeos/síntese química , Pirimidinas/síntese química , 8-Hidroxi-2'-Desoxiguanosina/química , Formamidas/química , Furanos/química , Oligonucleotídeos/química , Oxirredução , Estresse Oxidativo , Pirimidinas/química
6.
J Med Chem ; 63(6): 3172-3187, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32125853

RESUMO

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Manutenção de Minicromossomo/metabolismo , Naftoquinonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Furanos/síntese química , Furanos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Eur J Med Chem ; 192: 112160, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32146375

RESUMO

A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against ß1, ß2 and ß5 subunits revealed that they acted selectively on ß5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 µM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 µg/L; AUC0-t, 680 µg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Furanos/farmacologia , Cetonas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células HCT116 , Humanos , Cetonas/síntese química , Cetonas/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
J Mycol Med ; 30(2): 100924, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32037102

RESUMO

Cryptococcus neoformans, an encapsulated fungal pathogen is evolving as a major threat to immune-compromised patients and rarely to healthy individuals also. The cell wall bound capsular polysaccharide, melanin pigment and biofilm formation are major virulence factors that are known to contribute to cryptococcal meningitis. In the present study, a furanone derivative, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6) was evaluated against biofilm of seven different strains of C. neoformans in melanized and non-melanized condition. In addition, the efficacy of compound-6 in activation of TLR-2, opsonophagocytosis, and modulation of cytokine expression during phagocytosis were studied. During the biofilm study, we found that moderate capsule size favored biofilm formation. Interestingly, the minimum biofilm eradication concentration (MBEC0.5) of melanized biofilm was found to be achieved at 1- to 1.7-fold higher MBEC0.5 of non-melanized cells. The maximum eradication of 77% and 69% of non-melanized and melanized biofilm were observed. The capsule size was reduced to half of its size with marked changes in morphology. Furthermore, expression of TLR2, iNOS and pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ were also facilitated by compound-6. The correlation analysis showed a positive correlation between phagocytosis and the expression of TLR-2, iNOS, IL-6, IL-12. Collectively, the significant effect of compound-6, anti-melanization activity, antibiofilmand effective immunomodulant could be an interesting dual strategy drug agonist against cryptococcal meningitis.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Proteínas Opsonizantes/fisiologia , Fagocitose/efeitos dos fármacos , Animais , Antifúngicos/síntese química , Antifúngicos/química , Cápsulas Bacterianas/efeitos dos fármacos , Cápsulas Bacterianas/fisiologia , Células Cultivadas , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus/fisiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/fisiologia , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Melaninas/metabolismo , Meningite Criptocócica/imunologia , Meningite Criptocócica/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Opsonizantes/metabolismo
9.
Org Biomol Chem ; 18(7): 1462-1475, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025679

RESUMO

Selective glycosylation of the C-6 fluorinated galactofuranosyl acceptor 2 was studied with four galactofuranosyl donors. It was highlighted that this electron-withdrawing atom strongly impacted the behavior of the acceptor, thus leading to unprecedented glycosylation pathways. Competition between expected glycosylation of 2, ring expansion of this acceptor and furanosylation, and intermolecular aglycon transfer was observed. Further investigation of the fluorinated synthetic compounds showed that the presence of fluorine atom contributed to increase the inhibition of the growth of Leishmania tarentolae, a non-pathogenic strain of Leishmania.


Assuntos
Antiprotozoários/farmacologia , Furanos/farmacologia , Galactosídeos/farmacologia , Leishmania/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Configuração de Carboidratos , Furanos/síntese química , Furanos/química , Galactosídeos/síntese química , Galactosídeos/química , Glicosilação , Testes de Sensibilidade Parasitária , Estereoisomerismo
10.
Eur J Med Chem ; 186: 111855, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740051

RESUMO

There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.


Assuntos
Furanos/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/antagonistas & inibidores , Células Cultivadas , Dano ao DNA , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Piridonas/química , Pirimidinas/biossíntese , Relação Estrutura-Atividade
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117534, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31685424

RESUMO

Two novel ruthenium(II) polypyridyl complexes, namely, [Ru(dmp)2(CAPIP)](ClO4)2 (Ru(II)-1) and [Ru(dmp)2(CFPIP)](ClO4)2 (Ru(II)-2), which respectively contain (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phen-anthroline (CAPIP) and (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline. (CFPIP), were first designed and characterized (dmp = 2,9-dimethyl-1,10-phenanthroline). DNA binding experiments indicated that Ru(II) complexes interact with CT DNA through intercalative mode. In addition, the complexes Ru(II)-1 and Ru(II)-2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 4.1 ±â€¯1.4 µM and 6.1 ±â€¯1.4 µM on the A549 cancer cells. These values indicated higher activity than CAPIP, CFPIP, cisplatin (8.2 ±â€¯1.4 µM) and other corresponding Ru(II) polypyridyl complexes. Furthermore, the Ru(II) complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. Significantly, complexes Ru(II)-1 and Ru(II)-2 induced A549 cells apoptosis was mediated by increase of ROS levels and dysfunction of mitochondria, and resulted in cell cycle arrest and increased anti-migration activity on A549 cells. Overall, these results indicated that complexes Ru(II)-1 and Ru(II)-2 could be suitable candidates for further investigation as a chemotherapeutic agent in the treatment of tumors.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Substâncias Intercalantes/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bovinos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/metabolismo , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Halogenação , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Piridinas/síntese química , Piridinas/química , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química
12.
Nat Prod Res ; 34(15): 2109-2115, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30835542

RESUMO

Furolignan-type natural products, possessing important biological properties, have been synthesized from a commercially available furan. The elaborated synthetic strategy is based on an innovative Friedel-Crafts reaction starting from an alcohol or a carboxylic acid and triflic anhydride as promoter. Through this synthetic strategy, furolignans having two different aryl groups have been obtained. The products have been evaluated for their antimicrobial properties on Gram positive and Gram negative bacteria, in order to compare their biological activities with those of natural analogues.


Assuntos
Antibacterianos/síntese química , Furanos/síntese química , Lignanas/química , Álcoois/química , Antibacterianos/química , Ácidos Carboxílicos/química , Furanos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Sulfonamidas/química
13.
Biosci Biotechnol Biochem ; 84(1): 25-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31516064

RESUMO

The Japanese orange fly, Bactrocera tsuneonis, infests various citrus crops. While male pheromone components accumulated in the rectal glands are well characterized for Bactrocera, but information regarding the chemical factors involved in the life cycles of B. tsuneonis remains scarce. Herein, several volatile chemicals including a γ-decalactone, (3R,4R)-3-hydroxy-4-decanolide [(3R,4R)-HD], were identified as major components, along with acetamide and spiroketals as minor components in the rectal gland complexes of male B. tsuneonis flies. The lactone (3R,4R)-HD was also identified in female rectal gland complexes. The amount of this compound in mature males was significantly higher than those observed in females and immature males. The lactone (3R,4R)-HD was detected in flies fed with sucrose only, indicating that this lactone is not derived from dietary sources during adulthood, but biosynthesized in vivo. The predominant accumulation of (3R,4R)-HD in mature males also suggests a possible role in reproductive behavior.


Assuntos
Lactonas/química , Glândula de Sal/química , Tephritidae/fisiologia , Acetamidas/síntese química , Acetamidas/química , Animais , Cromatografia Gasosa , Citrus , Dieta , Feminino , Furanos/síntese química , Furanos/química , Japão , Lactonas/síntese química , Masculino , Espectrometria de Massas , Reprodução/fisiologia , Atrativos Sexuais/química , Comportamento Sexual Animal/fisiologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Sacarose
14.
Molecules ; 24(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817136

RESUMO

Efficient one-pot synthesis of new series of furylpyrazolino[60]fullerene derivatives was prepared by [3 + 2] cycloaddition reaction mediated with (diacetoxyiodo)benzene (PhI(OAc)2) as an oxidant in o-dichlorobenzene (ODCB) under microwave irradiation. Different techniques have been used to confirm the structural identity including FT-IR, fast atom bombardment (FAB)-mass, NMR, and single-crystal X-ray diffraction, in addition to investigating the photophysical properties and the electrochemical properties for the new compounds using UV-Vis spectra, fluorescence spectra, cyclic voltammetry, and square wave voltammetry. Three of these pyrazolino[60]fullerene compounds showed better electron affinity than the parent C60 in the ground state.


Assuntos
Eletroquímica/métodos , Fulerenos/química , Furanos/síntese química , Micro-Ondas , Pirazóis/síntese química , Cristalografia por Raios X , Furanos/química , Conformação Molecular , Oxirredução , Pirazóis/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Temperatura
15.
Chem Res Toxicol ; 32(12): 2488-2498, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31799839

RESUMO

Cytochrome P450 4B1 (CYP4B1) has been explored as a candidate enzyme in suicide gene systems for its ability to bioactivate the natural product 4-ipomeanol (IPO) to a reactive species that causes cytotoxicity. However, metabolic limitations of IPO necessitate discovery of new "pro-toxicant" substrates for CYP4B1. In the present study, we examined a series of synthetically facile N-alkyl-3-furancarboxamides for cytotoxicity in HepG2 cells expressing CYP4B1. This compound series maintains the furan warhead of IPO while replacing its alcohol group with alkyl chains of varying length (C1-C8). Compounds with C3-C6 carbon chain lengths showed similar potency to IPO (LD50 ≈ 5 µM). Short chain analogs (<3 carbons) and long chain analogs (>6 carbons) exhibited reduced toxicity, resulting in a parabolic relationship between alkyl chain length and cytotoxicity. A similar parabolic relationship was observed between alkyl chain length and reactive intermediate formation upon trapping of the putative enedial as a stable pyrrole adduct in incubations with purified recombinant rabbit CYP4B1 and common physiological nucleophiles. These parabolic relationships reflect the lower affinity of shorter chain compounds for CYP4B1 and increased ω-hydroxylation of the longer chain compounds by the enzyme. Furthermore, modest time-dependent inhibition of CYP4B1 by N-pentyl-3-furancarboxamide was completely abolished when trapping agents were added, demonstrating escape of reactive intermediates from the enzyme after bioactivation. An insulated CYP4B1 active site may explain the rarely observed direct correlation between adduct formation and cell toxicity reported here.


Assuntos
Amidas/toxicidade , Hidrocarboneto de Aril Hidroxilases/metabolismo , Furanos/toxicidade , Ativação Metabólica , Amidas/síntese química , Amidas/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/química , Domínio Catalítico , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/toxicidade , Furanos/síntese química , Furanos/metabolismo , Células Hep G2 , Humanos , Hidroxilação , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Coelhos , Relação Estrutura-Atividade , Terpenos/química , Terpenos/toxicidade
16.
Molecules ; 24(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847286

RESUMO

Highly functionalized furans are the key scaffolds of many pharmaceuticals and bioactive natural products. Herein, we disclose a new fruitful synthesis of polyfunctionalized furans starting from ß-nitroenones and α-functionalized ketones. The protocol involves two steps promoted by solid supported species, and it provides the title targets from satisfactory to very good overall yields and in an excellent diastereomeric ratios.


Assuntos
Furanos/síntese química , Ciclização , Furanos/química , Estrutura Molecular , Estereoisomerismo
17.
Org Lett ; 21(24): 9934-9939, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31815495

RESUMO

The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.


Assuntos
Alquinos/química , Éteres/síntese química , Furanos/síntese química , Compostos Organometálicos/química , Platina/química , Piranos/síntese química , Catálise , Éteres/química , Furanos/química , Estrutura Molecular , Piranos/química , Estereoisomerismo
18.
J Am Chem Soc ; 141(48): 18958-18963, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31744291

RESUMO

Herein we report a direct vicinal difunctionalization of thiophenes via the palladium/norbornene (Pd/NBE) cooperative catalysis. A series of mono- and disubstituted thiophenes can be difunctionalized site-selectively and regioselectively at the C4 and C5 positions in good yields, enabled by an arsine ligand and a unique amide-based NBE. The synthetic utility has been shown in derivatizations of complex bioactive compounds and an open-flask gram-scale preparation. Preliminary results have been obtained in the difunctionalization of furans and a direct C4-selective arylation of 2-substituted thiophenes.


Assuntos
Norbornanos/química , Paládio/química , Tiofenos/química , Arsenicais/síntese química , Arsenicais/química , Catálise , Furanos/síntese química , Furanos/química , Norbornanos/síntese química , Estereoisomerismo , Tiofenos/síntese química
19.
Molecules ; 24(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658589

RESUMO

Acting as a "green" manufacturing route, the enzyme toolbox made up of galactose oxidase, catalase, and horseradish peroxidase can achieve a satisfactory yield of 2,5-diformylfuran derived from 30 mM hydroxymethylfurfural. However, as the concentration of hydroxymethylfurfural increases, the substrate causes oxidative damage to the activity of the tri-enzyme system, and the accumulated hydrogen peroxide produced by galactose oxidase causes tri-enzyme inactivation. The cost of tri-enzymes is also very high. These problems prevent the utilization of this enzyme toolbox in practice. To address this, galactose oxidase, catalase, and horseradish peroxidase were co-immobilized into Cu3(PO4)2 nanoflowers in this study. The resulting co-immobilized tri-enzymes possessed better tolerance towards the oxidative damage caused by hydroxymethylfurfural at high concentrations, as compared to free tri-enzymes. Moreover, the 2,5-diformylfuran yield of co-immobilized tri-enzymes (95.7 ± 2.7%) was 1.06 times higher than that of separately immobilized enzymes (90.4 ± 1.9%). This result could be attributed to the boosted protective effect provided by catalase to the activity of galactose oxidase, owing to the physical proximity between them on the same support. After 30 recycles, co-immobilized tri-enzymes still achieves 86% of the initial yield. Moreover, co-immobilized tri-enzymes show enhanced thermal stability compared with free tri-enzymes. This work paves the way for the production of 2,5-diformylfuran from hydroxymethylfurfural via co-immobilized tri-enzymes.


Assuntos
Catalase/química , Enzimas Imobilizadas/química , Furaldeído/análogos & derivados , Furanos/síntese química , Glucose Oxidase/química , Furaldeído/química , Peroxidase do Rábano Silvestre/química , Oxirredução
20.
Nature ; 575(7784): 643-646, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31618759

RESUMO

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1-4. Antagonism of γ-aminobutyric acid A receptors (GABAARs) by bilobalide has been linked to the rescue of cognitive deficits in mouse models of Down syndrome5. A lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target4; however, steric congestion and the instability of bilobalide1,2,6 have prevented pull-down of biological targets other than the GABAΑRs. A concise and flexible synthesis of bilobalide would facilitate the development of probes for the identification of potential new targets, analogues with differential selectivity between insect and human GABAΑRs, and stabilized analogues with an enhanced serum half-life7. Here we exploit the unusual reactivity of bilobalide to enable a late-stage deep oxidation that symmetrizes the molecular core and enables oxidation states to be embedded in the starting materials. The same overall strategy may be applicable to G. biloba congeners, including the ginkgolides-some of which are glycine-receptor-selective antagonists8. A chemical synthesis of bilobalide should facilitate the investigation of its biological effects and its therapeutic potential.


Assuntos
Ciclopentanos/síntese química , Furanos/síntese química , Ginkgolídeos/síntese química , Técnicas de Química Analítica , Ginkgo biloba/química , Oxirredução
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