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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.
Chemistry ; 30(46): e202401955, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-38860572

RESUMEN

In response to the pressing global challenge of antibiotic resistance, time efficient design and synthesis of novel antibiotics are of immense need. Polycyclic polyprenylated acylphloroglucinols (PPAP) were previously reported to effectively combat a range of gram-positive bacteria. Although the exact mode of action is still not clear, we conceptualized a late-stage divergent synthesis approach to expand our natural product-based PPAP library by 30 additional entities to perform SAR studies against methicillin-resistant Staphylococcus aureus (MRSA). Although at this point only data from cellular assays are available and understanding of molecular drug-target interactions are lacking, the experimental data were used to generate 3D-QSAR models via an artificial intelligence training and to identify a common pharmacophore model. The experimentally validated QSAR model enabled the estimation of anti-MRSA activities of a virtual compound library consisting of more than 100,000 in-silico generated B PPAPs, out of which the 20 most promising candidates were synthesized. These novel PPAPs revealed significantly improved cellular activities against MRSA with growth inhibition down to concentrations less than 1 µm.


Asunto(s)
Antibacterianos , Productos Biológicos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Floroglucinol , Relación Estructura-Actividad Cuantitativa , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/síntesis química , Floroglucinol/química , Floroglucinol/farmacología , Floroglucinol/síntesis química , Diseño de Fármacos , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/síntesis química
3.
J Org Chem ; 89(11): 8084-8098, 2024 06 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.
Org Biomol Chem ; 22(39): 8037-8047, 2024 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-39263808

RESUMEN

Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market for a variety of applications, but one notable omission is that of tetraasteranes, which are homologues of cubanes belonging to a class of polycyclic hydrocarbon cage compounds. Tetraasteranes exhibit potential as scaffolds in drug discovery due to their identical cyclobutane structures and rigid conformation resembling cubanes. Based on the studies of the physical and chemical properties of tetraasteranes by density functional theory, three series of compounds were designed as homologues of cubanes by the substitution of cubane scaffolds in pharmaceuticals with tetraasteranes. Their potential for pharmaceutical applications was evaluated in silico by molecular docking and dynamics simulations. Their pharmacokinetic and physicochemical properties were studied by the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The results indicate that tetraasteranes may be scaffolds as novel bioisosteres of cubanes, as well as hydrogen bond donors or acceptors, which enhance the affinity between ligands and receptors with more stable binding behavior and feasible tolerability in ADMET. All these findings provide new opportunities for tetraasteranes to serve as effective pharmaceutical scaffolds for drug discovery and to accelerate the drug discovery process by repurposing both new and old commercial compounds.


Asunto(s)
Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Humanos , Teoría Funcional de la Densidad , Simulación de Dinámica Molecular , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Estructura Molecular
5.
Macromol Rapid Commun ; 45(20): e2400399, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38867361

RESUMEN

A novel polycyclic naphthoxazine resin (NSA-thiq) is synthesized via N, O-acetal forming reaction between o-hydroxyl naphthaldehyde and 1,2,3,4-tetrahydroisoquinoline. The chemical structure of the monomer is investigated and confirmed by 1H and 13C NMR, Fourier-transform infrared (FT-IR) spectroscopy, and high-resolution mass spectrometry. Besides, the ring-opening polymerization behavior similar to ordinary benzoxazine resins is observed by differential scanning calorimetry (DSC) and in situ FT-IR analyses, leading to the formation of the phenolic cross-linked network. Notably, DSC thermograms indicate that the newly obtained polycyclic naphthoxazine resin exhibits much lower polymerization temperatures compared to many other reported benzoxazine or naphthoxazine resins. Moreover, the corresponding polybenzoxazine (poly(NSA-thiq)) shows comparable thermal stability in comparison with thermosets derived from monobenzoxazine resins. As a consequence of these unique performances, NSA-thiq is applied as a property modifier for a commercialized benzoxazine resin (BA-a). The glass transition temperature of copolymeric thermosets is enhanced without sacrificing too much thermal stability and heat resistance. Here, another series of naphthoxazine thermosetting resin is explored, which can provide more examples for constructing composites based on thermoset polymers.


Asunto(s)
Polimerizacion , Estructura Molecular , Oxazinas/química , Temperatura , Espectroscopía Infrarroja por Transformada de Fourier , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Benzoxazinas/química , Benzoxazinas/síntesis química , Resinas Sintéticas/química , Rastreo Diferencial de Calorimetría , Polímeros/química , Polímeros/síntesis química
6.
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
7.
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
8.
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
9.
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
10.
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
11.
J Am Chem Soc ; 143(2): 983-991, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33377771

RESUMEN

Here we report the synthesis of two polyhelicene frameworks consisting, from end-to-end, of 18 and 24 fused benzene rings. The latter exhibits the largest electronic circular dichroism in the visible spectrum of any molecule. These shape-persistent helical nanoribbons incorporate multiple helicenes, a class of contorted polycyclic aromatic molecules consisting of ortho-annulated rings. These conjugated, chiral molecules have interesting chemical, biological, and chiroptical properties; however, there are very few helicenes with extraordinary chiroptical response over a broad range of the visible spectrum-a key criterion for applications such as chiral optoelectronics. In this report, we show that coupling the polyhelicene framework with multiple perylene-diimide subunits elicits a significant chiroptic response. Notably, the molar circular dichroism increases faster than the absorptivity of these molecules as their helical axis lengthens. Computational analysis reveals that the greatly amplified circular dichroism arises from exciton-like interactions between the perylene-diimide and the helicene moieties. We predict that even greater chiroptic enhancement will result from further axial elongation of these nanoribbons, which can be readily enabled via the iterative synthetic method presented herein.


Asunto(s)
Nanoestructuras/química , Compuestos Policíclicos/química , Teoría Funcional de la Densidad , Estructura Molecular , Compuestos Policíclicos/síntesis química , Estereoisomerismo
12.
Anal Chem ; 93(3): 1507-1514, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33356164

RESUMEN

Cryptophane host molecules provide ultrasensitive contrast agents for 129Xe NMR/MRI. To investigate key features of cryptophane-Xe sensing behavior, we designed a novel water-soluble cryptophane with a pendant hydrophobic adamantyl moiety, which has good affinity for a model receptor, beta-cyclodextrin (ß-CD). Adamantyl-functionalized cryptophane-A (AFCA) was synthesized and characterized for Xe affinity, 129Xe NMR signal, and aggregation state at varying AFCA and ß-CD concentrations. The Xe-AFCA association constant was determined by fluorescence quenching, KA = 114,000 ± 5000 M-1 at 293 K, which is the highest reported affinity for a cryptophane host in phosphate-buffered saline (pH 7.2). No hyperpolarized (hp) 129Xe NMR peak corresponding to AFCA-bound Xe was directly observed at high (100 µM) AFCA concentration, where small cryptophane aggregates were observed, and was only detected at low (15 µM) AFCA concentration, where the sensor remained fully monomeric in solution. Additionally, we observed no change in the chemical shift of AFCA-encapsulated 129Xe after ß-CD binding to the adamantyl moiety and a concomitant lack of change in the size distribution of the complex, suggesting that a change in the aggregation state is necessary to elicit a 129Xe NMR chemical shift in cryptophane-based sensing. These results aid in further elucidating the recently discovered aggregation phenomenon, highlight limitations of cryptophane-based Xe sensing, and offer insights into the design of monomeric, high-affinity Xe sensors.


Asunto(s)
Compuestos Policíclicos/química , Xenón/química , beta-Ciclodextrinas/química , Técnicas Biosensibles , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Estructura Molecular , Compuestos Policíclicos/síntesis química , Isótopos de Xenón
13.
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
14.
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
15.
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
16.
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
17.
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
18.
Chembiochem ; 21(4): 531-542, 2020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-31339225

RESUMEN

There is a current surge of interest in the development of novel photosensitizers (PSs) for photodynamic therapy (PDT), as those currently approved are not completely ideal. Among the tested compounds, we have previously investigated the use of RuII polypyridyl complexes with a [Ru(bipy)2 (dppz)]2+ and [Ru(phen)2 (dppz)]2+ scaffold (bipy=2,2'-bipyridine; dppz=dipyrido[3,2-a:2',3'-c]phenazine; phen=1,10-phenanthroline). These complexes selectively target DNA. However, because DNA is ubiquitous, it would be of great interest to increase the selectivity of our PDT PSs by linking them to a targeting vector in view of targeted PDT. Herein, we present the synthesis, characterization, and in-depth photophysical evaluation of a nanobody-containing RuII polypyridyl conjugate selective for the epidermal growth factor receptor (EGFR) in view of targeted PDT. Using ICP-MS and confocal microscopy, we could demonstrate that our conjugate has high selectivity for the EGFR receptor, which is a crucial oncological target because it is overexpressed and/or deregulated in a variety of solid tumors. However, in contrast to expectations, this conjugate was found to not produce reactive oxygen species (ROS) in cancer cells and is therefore not phototoxic.


Asunto(s)
Neoplasias/tratamiento farmacológico , Compuestos Organometálicos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Compuestos Policíclicos , Rutenio/química , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Humanos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química
19.
Bioorg Med Chem Lett ; 30(7): 126969, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32014384

RESUMEN

In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.


Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Compuestos Policíclicos/farmacología , Antibacterianos/síntesis química , Diterpenos/síntesis química , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Policíclicos/síntesis química , Staphylococcus epidermidis/efectos de los fármacos , Relación Estructura-Actividad , Pleuromutilinas
20.
Bioorg Med Chem Lett ; 30(16): 127354, 2020 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-32631552

RESUMEN

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC50 values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Ciclooctanos/farmacología , Lignanos/farmacología , Compuestos Policíclicos/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclooctanos/síntesis química , Ciclooctanos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Lignanos/síntesis química , Lignanos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Polimerizacion/efectos de los fármacos , Schisandra/química , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química
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