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1.
J Am Chem Soc ; 146(28): 18967-18978, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-38973592

RESUMEN

Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.


Asunto(s)
Adamantano , Aminobenzoatos , Aminofenoles , Anilidas , Compuestos Policíclicos , Aminofenoles/química , Aminofenoles/farmacología , Aminofenoles/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/síntesis química , Adamantano/química , Adamantano/farmacología , Adamantano/síntesis química , Adamantano/análogos & derivados , Anilidas/farmacología , Anilidas/química , Anilidas/síntesis química , Aminobenzoatos/farmacología , Aminobenzoatos/química , Aminobenzoatos/síntesis química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Estructura Molecular , Reacción de Cicloadición , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química
2.
Nat Commun ; 15(1): 5879, 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-38997253

RESUMEN

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.


Asunto(s)
Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Xantenos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Xantenos/síntesis química , Xantenos/farmacología , Xantenos/química , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Descubrimiento de Drogas , Estructura Molecular
3.
J Org Chem ; 89(11): 8084-8098, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38810000

RESUMEN

A facile and novel synthetic method for the synthesis of functionalized polycyclic coumarins at the C-4 and C-5 positions is proposed for the first time, which employs copper-catalyzed addition reactions of undiscovered alkenes with difluoromethyl radicals to construct polycyclic coumarins. This strategy is characterized by high regioselectivity, easy availability of raw materials, and simple operation. Additionally, such undiscovered coumarin alkenes can be reacted with a variety of difluoromethyl precursors to obtain a wide range of valuable C-4 and C-5 position functionalized/difluoromethylated polycyclic coumarins. More importantly, some of the products showed significant inhibition of proliferation in vitro against melanoma B16-F10 and lung cancer A549 cell lines with optimal IC50 values of 8.57 and 16.04 µM, respectively.


Asunto(s)
Cobre , Cumarinas , Cumarinas/química , Cumarinas/síntesis química , Catálisis , Cobre/química , Humanos , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química
4.
Chem Biol Drug Des ; 103(6): e14554, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38806405

RESUMEN

This paper reports the design, synthesis, and antibacterial activity study of pleuromutilin derivatives with 2-methyl-4-nitroaniline and 2-methoxy-4-nitroaniline side chains at the C22 position. The structures of the new compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The inhibitory activity of the compounds against MSSA, pyogeniccoccus, streptococcus, and MRSA strains was determined using the micro broth dilution method. The results showed that the compounds exhibited certain activity against Gram-positive bacteria, among which compounds A8a, A8b, A8c, A8d, and A7 demonstrated superior antibacterial activity against MSSA, MRSA, and pyogeniccoccus compared to tiamulin, although the derivatives showed lower antibacterial activity against streptococcus compared to the control drug. Based on the favorable in vitro activity of A8c, the time-kill kinetics against MRSA were evaluated, revealing that compound A8c could inhibit bacterial proliferation in a concentration-dependent manner.


Asunto(s)
Antibacterianos , Diterpenos , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Pleuromutilinas , Compuestos Policíclicos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Relación Estructura-Actividad , Streptococcus/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos
5.
Bioorg Chem ; 146: 107289, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38493636

RESUMEN

Structurally diverse cyclopenta[4,5]pyrrolo[1,2-a]indoles heterocycles were smoothly constructed in good to excellent yields (up to 99 %) with excellent diastereoselectivities (>19:1 dr) through a novel and facile strategy based on BF3-catalyzed Friedel-Crafts alkylation/Aldol/Dehydrative cyclization cascade reaction. The anti-proliferative activity of these newly synthesized polycyclic indoles was screened, and all the functionalized reductive derivatives exhibited favorable anti-tumor activity. Notably, compound 4ae displayed the remarkable inhibitory activity against MCF-7 and HeLa cells with IC50 values of 4.62 µM and 7.71 µM, respectively. Mechanistically, the representative compound 4ae could effectively induce apoptosis of MCF-7 cells in crediting to up-regulate the relative expression of apoptotic protein BAX/Bcl-2, subsequently activate Pro-caspase 9 and cleave PARP, simultaneously block the cell cycle through down- and up-regulate the expression of cyclin B1 and p53, respectively. Moreover, compound 4ae also exhibited promising antineoplastic efficacy in subcutaneous MCF-7 xenograft mice which manifest significant shrunken tumors conspicuous nuclear apoptotic signal and minimal systemic toxicity. This strategy not only established a novel and efficient method for the assembly of structurally complex indole heterocycles, but also provided a series of compounds possessing attractive anti-cancer activity, which holds immense potential for future biomedical applications.


Asunto(s)
Antineoplásicos , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Indoles/farmacología , Células MCF-7 , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología
6.
J Enzyme Inhib Med Chem ; 37(1): 252-268, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34933639

RESUMEN

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Simulación del Acoplamiento Molecular , Nitrógeno/farmacología , Compuestos Policíclicos/farmacología , Timidina Fosforilasa/antagonistas & inhibidores , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Estructura Molecular , Nitrógeno/química , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Relación Estructura-Actividad , Timidina Fosforilasa/metabolismo
7.
Eur J Med Chem ; 227: 113919, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34688010

RESUMEN

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ciclooctanos/farmacología , Hígado/efectos de los fármacos , Compuestos Policíclicos/farmacología , Sustancias Protectoras/farmacología , Animales , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A , Ciclooctanos/síntesis química , Ciclooctanos/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Interleucina-6/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Sustancias Protectoras/síntesis química , Sustancias Protectoras/química , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad
8.
Small Methods ; 5(11): e2100770, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34927965

RESUMEN

Immune and targeted therapy are becoming the first-line treatment for renal cell carcinoma (RCC). However, therapeutic outcomes are limited due to the low efficiency and side effect. Here, it is found that helicenes are able to exhibit an anticancer capability through changing the molecular structure from planar to nonplanar. Furthermore, the cytotoxicity in vitro and cancer inhibition ability of nonplanar helicenes increase with its aromatic rings' number. It is further demonstrated that benzo[4]helicenium shows the specific killing efficiency against the RCC cancer as compared to normal kidney cells. This is majorly originated from a more selective damage of benzo[4]helicenium for mitochondria and DNA in RCC cancer cells, not the normal kidney. The selective killing ability of benzo[4]helicenium makes it have potential to be used as a targeted drug for the precise treatment of RCC.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Perfilación de la Expresión Génica/métodos , Neoplasias Renales/tratamiento farmacológico , Hidrocarburos Policíclicos Aromáticos/síntesis química , Compuestos Policíclicos/síntesis química , Animales , Carcinoma de Células Renales/genética , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Humanos , Neoplasias Renales/genética , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Hidrocarburos Policíclicos Aromáticos/química , Hidrocarburos Policíclicos Aromáticos/farmacología , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , RNA-Seq , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Enzyme Inhib Med Chem ; 36(1): 2087-2103, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34823417

RESUMEN

Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5∼1 µg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10-8∼5.10 × 10-5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be -12.0 kcal/mol.


Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Simulación del Acoplamiento Molecular , Compuestos Policíclicos/farmacología , Resonancia por Plasmón de Superficie , Antibacterianos/síntesis química , Antibacterianos/química , Química Clic , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Pleuromutilinas
10.
Org Lett ; 23(18): 7118-7122, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34491766

RESUMEN

An efficient tandem nucleophilic aminopalladation and carbene insertion sequence is described for the synthesis of indole fused polycycles. The reaction process provides a variety of substituted indeno[1,2-b]indoles in up to 99% yields.


Asunto(s)
Indoles/química , Metano/análogos & derivados , Compuestos Policíclicos/síntesis química , Ciclización , Indoles/síntesis química , Metano/química , Estructura Molecular , Compuestos Policíclicos/química
11.
Sci Rep ; 11(1): 15750, 2021 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-34344971

RESUMEN

Novel tri-and tetra-cyclic compounds based on the thiadiazolopyrimidine ring system were synthesized, and their antimicrobial activity was estimated. The obtained results evidenced the substantial efficiencies of pyrano-thiadiazolopyrimidine compounds 8a-b and 9a-b toward the two strains of gram-positive bacteria (S. aureus and B. cereus). Besides, tetracyclic pyrazolopyrimido-thiadiazolopyrimidine derivatives 16a-b and 17a-b displayed prominent efficiencies toward the two strains of gram-negative bacteria (E. coli and P. aeruginosa). In addition, compounds 8a-b and 9a-b displayed good efficacy toward C. albicans. The activity of antiquorum sensing (anti-QS) inhibition of the newly synthesized thiadiazolopyrimidine-based compounds toward C. violaceum was tested, suggesting satisfactory activity for derivatives 16a-b, 17a-b, 8b, and 9a. The cytotoxic activity of these derivatives was screened toward various cancer cell lines (MCF-7, PC3, Hep-2, and HepG2) and standard normal fibroblast cells (WI38) by utilizing the MTT assay. The pyrazolopyrimido-thiadiazolopyrimidine derivatives 16a, 16b17a, and 17b showed potent cytotoxic efficacy against the MCF-7 cells with the IC50 values ranging from 5.69 to 9.36 µM. Also, the endorsed structural activity relationship (SAR) of the inspected thiadiazolopyrimidine derivatives provided a correlation between the chemical structure and anticancer efficiency. The in silico docking studies were implemented for silencing the hormonal signaling in the breast (PDB Code-5NQR). The results were found to be consistent with the cytotoxic activity.


Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Pirimidinas/química , Tiadiazoles/química , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Bacterias/efectos de los fármacos , Proliferación Celular , Hongos/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Tumorales Cultivadas
12.
Yakugaku Zasshi ; 141(8): 985-994, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34334550

RESUMEN

On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.


Asunto(s)
Alcaloides/síntesis química , Productos Biológicos/síntesis química , Ciclopropanos/síntesis química , Compuestos Policíclicos/síntesis química , Alcaloides/química , Productos Biológicos/química , Carbolinas/síntesis química , Carbolinas/química , Ciclización , Ciclopropanos/química , Humanos , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/química , Indoles/síntesis química , Indoles/química , Aspergilosis Pulmonar Invasiva/metabolismo , Compuestos Policíclicos/química
13.
Eur J Med Chem ; 223: 113624, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34153574

RESUMEN

A series of pleuromutilin derivatives with 1,2,4-triazole-3-substituted Schiff base structure were designed and synthesized under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against 4 strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus 144 and S.aureus AD3) and 1 strain of E. coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, compound 60 exhibited superior in vitro antibacterial effect against MRSA (MIC = 0.25 µg/mL) than tiamulin (MIC = 0.5 µg/mL), and compound 60 (-2.28 log10 CFU/mL) also displayed superior in vivo antibacterial efficacy than tiamulin (-1.40 log10 CFU/mL) in reducing MRSA load in the mouse thigh infection model. The time-kill study and the post-antibiotic effect study indicated that compound 60 showed a faster bactericidal kinetic and longer PAE time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 4.06 and 4.27 h) against MRSA compared with tiamulin (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.72 and 2.14 h). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and HepG2 cells at the concentration of 4 µg/mL. Additionally, the development of resistance study showed that MRSA did not easily develop resistance against compound 60 compared with tiamulin after induction for 8 passages.


Asunto(s)
Antibacterianos/uso terapéutico , Diterpenos/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Compuestos Policíclicos/uso terapéutico , Bases de Schiff/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Diseño de Fármacos , Femenino , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Bases de Schiff/síntesis química , Bases de Schiff/farmacología , Pleuromutilinas
14.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33946609

RESUMEN

Hydrogen-bonded organic frameworks (HOFs) are the focus of intense scientific research due their potential applications in science and technology. Here, we report on the synthesis, characterization, and photobehavior of a new HOF (T12F-1(124TCB)) based on a dehydrobenzoannulene derivative containing fluorine atoms (T12F-COOH). This HOF exhibits a 2D porous sheet, which is hexagonally networked via H-bonds between the carboxylic groups, and has an interlayers distance (4.3 Å) that is longer than that of a typical π-π interaction. The presence of the fluorine atoms in the DBA molecular units largely increases the emission quantum yield in DMF (0.33, T12F-COOH) when compared to the parent compound (0.02, T12-COOH). The time-resolved dynamics of T12F-COOH in DMF is governed by the emission from a locally excited state (S1, ~ 0.4 ns), a charge-transfer state (S1(CT), ~ 2 ns), and a room temperature emissive triplet state (T1, ~ 20 ns), in addition to a non-emissive triplet structure with a charge-transfer character (T1(CT), τ = 0.75 µs). We also report on the results using T12F-ester. Interestingly, FLIM experiments on single crystals unravel that the emission lifetimes of the crystalline HOF are almost twice those of the amorphous ones or the solid T12F-ester sample. This shows the relevance of the H-bonds in the photodynamics of the HOF and provides a strong basis for further development and study of HOFs based on DBAs for potential applications in photonics.


Asunto(s)
Alquinos/química , Flúor/química , Compuestos Policíclicos/química , Alquinos/síntesis química , Técnicas de Química Sintética , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Procesos Fotoquímicos , Compuestos Policíclicos/síntesis química
15.
Bioorg Chem ; 112: 104956, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33991838

RESUMEN

A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85-110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.


Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Simulación del Acoplamiento Molecular , Oxadiazoles/farmacología , Compuestos Policíclicos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxadiazoles/química , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Relación Estructura-Actividad , Pleuromutilinas
16.
Bioorg Med Chem ; 38: 116138, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33857737

RESUMEN

A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC50 = 3.95 µM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.


Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Compuestos Policíclicos/farmacología , Subunidades Ribosómicas Grandes Bacterianas/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Células RAW 264.7 , Relación Estructura-Actividad , Pleuromutilinas
17.
Acc Chem Res ; 54(8): 1843-1855, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33793197

RESUMEN

Natural products are biosynthesized from a limited pool of starting materials via pathways that obey the same chemical logic as textbook organic reactions. Given the structure of a natural product, it is therefore often possible to predict its likely biosynthesis. Although biosynthesis mainly occurs in the highly specific chemical environments of enzymes, the field of biomimetic total synthesis attempts to replicate predisposed pathways using chemical reagents.We have followed several guidelines in our biomimetic approach to total synthesis. The overarching aim is to construct the same skeletal C-C and C-heteroatom bonds and in the same order as our biosynthetic hypothesis. In order to explore the innate reactivity of (bio)synthetic intermediates, the use of protecting groups is avoided or at least minimized. The key step, which is usually a cascade reaction, should be predisposed to selectively generate molecular complexity under substrate control (e.g., cycloadditions, radical cyclizations, carbocation rearrangements). In general, simple reagents and mild conditions are used; many of the total syntheses presented in this Account could be achieved using pre-1980s methodology. We have focused almost exclusively on the synthesis of meroterpenoids, that is, natural products of mixed terpene and aromatic polyketide origin, using commercially available terpenes and electron-rich aromatic compounds as starting materials. Finally, all of the syntheses in this Account involve a dearomatization step as a means to trigger a cascade reaction or to construct stereochemical complexity from a planar, aromatic intermediate.A biomimetic strategy can offer several advantages to a total synthesis project. Most obviously, successful biomimetic syntheses are usually concise and efficient, naturally adhering to the atom, step, and redox economies of synthesis. For example, in this Account, we describe a four-step synthesis of garcibracteatone and a three-step synthesis of nyingchinoid A. It is difficult to imagine shorter, non-biomimetic syntheses of these intricate molecules. Furthermore, biomimetic synthesis gives insight into biosynthesis by revealing the chemical relationships between biosynthetic intermediates. Access to these natural substrates allows collaboration with biochemists to help uncover the function of newly discovered enzymes and elucidate biosynthetic pathways, as demonstrated in our work on the napyradiomycin family. Third, by making biosynthetic connections between natural products, we can sometimes highlight incorrect structural assignments, and herein we discuss structure revisions of siphonodictyal B, rasumatranin D, and furoerioaustralasine. Last, biomimetic synthesis motivates the prediction of "undiscovered natural products" (i.e., missing links in biosynthesis), which inspired the isolation of prenylbruceol A and isobruceol.


Asunto(s)
Productos Biológicos/síntesis química , Biomimética/métodos , Terpenos/síntesis química , Benzopiranos/síntesis química , Benzopiranos/química , Productos Biológicos/química , Ciclización , Reacción de Cicloadición , Oxidación-Reducción , Floroglucinol/síntesis química , Floroglucinol/química , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Terpenos/química
18.
J Enzyme Inhib Med Chem ; 36(1): 764-775, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33733986

RESUMEN

Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 µg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate π-π stacking between molecules and surrounding residues.


Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Simulación del Acoplamiento Molecular , Compuestos Policíclicos/farmacología , Urea/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Diterpenos/síntesis química , Diterpenos/química , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Urea/análogos & derivados , Urea/química , Pleuromutilinas
19.
J Am Chem Soc ; 143(12): 4661-4667, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33735570

RESUMEN

π-Extended helicenes constitute an important class of polycyclic aromatic hydrocarbons with intrinsic chirality. Herein, we report the syntheses of π-extended [7]helicene 4 and π-extended [9]helicene 6 through regioselective cyclodehydrogenation in high yields, where a "prefusion" strategy plays a key role in preventing undesirable aryl rearrangements. The unique helical structures are unambiguously confirmed by X-ray crystal structure analysis. Compared to the parent pristine [7]helicene and [9]helicene, these novel π-extended helicenes display significantly improved photophysical properties, with a quantum yield of 0.41 for 6. After optical resolution by chiral high-performance liquid chromatography, the chiroptical properties of enantiomers 4-P/M and 6-P/M are investigated, revealing that the small variation in helical length from [7] to [9] can cause an approximately 10-fold increase in the dissymmetry factors. The circularly polarized luminescence brightness of 6 reaches 12.6 M-1 cm-1 as one of the highest among carbohelicenes.


Asunto(s)
Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo
20.
Chem Rev ; 121(7): 4045-4083, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33576620

RESUMEN

Ruthenium-catalyzed cycloadditions to form five-, six-, and seven-membered rings are summarized, including applications in natural product total synthesis. Content is organized by ring size and reaction type. Coverage is limited to processes that involve formation of at least one C-C bond. Processes that are stoichiometric in ruthenium or exploit ruthenium as a Lewis acid (without intervention of organometallic intermediates), ring formations that occur through dehydrogenative condensation-reduction, σ-bond activation-initiated annulations that do not result in net reduction of bond multiplicity, and photochemically promoted ruthenium-catalyzed cycloadditions are not covered.


Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Organometálicos/química , Compuestos Policíclicos/síntesis química , Rutenio/química , Catálisis , Ciclización , Oxidación-Reducción , Procesos Fotoquímicos , Estereoisomerismo
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