RESUMO
Arylsulfonyl group-bearing α,ß-unsaturated enol esters were readily assembled via the Cs2CO3-mediated union of 2-bromoallyl sulfones and cinnamic acids. The overall transformation is equivalent to an sp2 carbon-oxygen coupling reaction, and therefore constitutes a formal vinylic substitution. Several of the products display promising levels of antiproliferative activities higher than that of the anticancer drug carboplatin. Thiophenol reacted with 2-bromoallyl sulfones under identical conditions to afford α-thiophenyl-α'-tosyl acetone via an apparent aerial oxidation.
Assuntos
Antineoplásicos , Proliferação de Células , Ésteres , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Humanos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Sulfonas/química , Sulfonas/farmacologia , Sulfonas/síntese química , Relação Estrutura-Atividade , Compostos de Vinila/química , Compostos de Vinila/farmacologia , Compostos de Vinila/síntese químicaRESUMO
A series of D-ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21-vinyl 20-keto-pregnene (2f) (IC50 = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)-positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17ß-estradiol-induced progesterone receptor expression. Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1.
Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , Receptor alfa de Estrogênio , Transdução de Sinais , Humanos , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Pregnenos/farmacologia , Pregnenos/síntese química , Pregnenos/química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos de Vinila/farmacologia , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
Aryl-substituted pyridine(diimine) iron complexes promote the catalytic [2 + 2] cycloadditions of alkenes and dienes to form vinylcyclobutanes as well as the oligomerization of butadiene to generate divinyl(oligocyclobutane), a microstructure of poly(butadiene) that is chemically recyclable. A systematic study on a series of iron butadiene complexes as well as their ruthenium congeners has provided insights into the essential features of the catalyst that promotes these cycloaddition reactions. Structural and computational studies on iron butadiene complexes identified that the structural rigidity of the tridentate pincer enables rare s-trans diene coordination. This geometry, in turn, promotes dissociation of one of the alkene arms of the diene, opening a coordination site for the incoming substrate to engage in oxidative cyclization. Studies on ruthenium congeners established that this step occurs without redox involvement of the pyridine(diimine) chelate. Cyclobutane formation occurs from a metallacyclic intermediate by reversible C(sp3)-C(sp3) reductive coupling. A series of labeling experiments with pyridine(diimine) iron and ruthenium complexes support the favorability of accessing the +3 oxidation state to trigger C(sp3)-C(sp3) reductive elimination, involving spin crossover from S = 0 to S = 1. The high density of states of iron and the redox-active pyridine(diimine) ligand facilitate this reactivity under thermal conditions. For the ruthenium congener, the pyridine(diimine) remains redox innocent and irradiation with blue light was required to promote the analogous reactivity. These structure-activity relationships highlight important design principles for the development of next generation catalysts for these cycloaddition reactions as well as the promotion of chemical recycling of cycloaddition polymers.
Assuntos
Alcadienos/química , Complexos de Coordenação/química , Catálise , Complexos de Coordenação/síntese química , Reação de Cicloadição , Ciclobutanos/síntese química , Ferro/química , Estrutura Molecular , Oxirredução , Rutênio/química , Estereoisomerismo , Relação Estrutura-Atividade , Compostos de Vinila/síntese químicaRESUMO
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 µM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
Assuntos
Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Sulfonas/farmacologia , Ácidos Sulfônicos/farmacologia , Tripanossomicidas/farmacologia , Compostos de Vinila/farmacologia , Animais , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/toxicidade , Ensaios Enzimáticos , Feminino , Células HeLa , Humanos , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ligação Proteica , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/metabolismo , Sulfonas/toxicidade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/metabolismo , Ácidos Sulfônicos/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/metabolismo , Compostos de Vinila/toxicidadeRESUMO
In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug-polymer system. Melt viscosity as a function of temperature was determined for the drug-polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.
Assuntos
Tecnologia de Extrusão por Fusão a Quente/métodos , Excipientes Farmacêuticos/síntese química , Povidona/síntese química , Pirrolidinas/síntese química , Fumarato de Quetiapina/síntese química , Compostos de Vinila/síntese química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Temperatura Alta , Oxirredução , Excipientes Farmacêuticos/farmacocinética , Povidona/farmacocinética , Pirrolidinas/farmacocinética , Fumarato de Quetiapina/farmacocinética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Compostos de Vinila/farmacocinéticaRESUMO
Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P. falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials.
Assuntos
Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Artemisininas/síntese química , Artemisininas/química , Artemisininas/farmacologia , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Heme/antagonistas & inibidores , Heme/metabolismo , Malária/metabolismo , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Organofosfonatos/farmacologia , Testes de Sensibilidade Parasitária , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos de Vinila/síntese química , Compostos de Vinila/química , Compostos de Vinila/farmacologiaRESUMO
Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H2O2-mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c, arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.
Assuntos
Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sulfonas/farmacologia , Compostos de Vinila/farmacologia , Animais , Antioxidantes/síntese química , Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Compostos de Vinila/síntese químicaRESUMO
We report a palladium-catalyzed, three-component carbosilylation reaction of internal symmetrical alkynes, silicon electrophiles, and primary alkyl zinc iodides. Depending on the choice of ligand, stereoselective synthesis of either cis- or trans-tetrasubstituted vinyl silanes is possible. We also demonstrate conditions for the Hiyama cross-coupling of these products to prepare geometrically defined tetrasubstituted alkenes.
Assuntos
Silanos/síntese química , Compostos de Vinila/síntese química , Alcinos/química , Catálise , Iodetos/química , Ligantes , Estrutura Molecular , Paládio/química , Silanos/química , Silício/química , Estereoisomerismo , Compostos de Vinila/química , Compostos de Zinco/químicaRESUMO
The discovery of safe, general, and practical procedures to prepare vinyl fluorides from readily available precursors remains a synthetic challenge. The metal-free hydrofluorination of alkynes constitutes an attractive though elusive strategy for their preparation. Introduced here is an inexpensive and easily handled reagent that enables the development of simple and scalable protocols for the regioselective hydrofluorination of alkynes to access both the E and Zâ isomers of vinyl fluorides. These reaction conditions were suitable for a diverse collection of alkynes, including several highly functionalized pharmaceutical derivatives. Computational and experimental mechanistic studies support C-F bond formation through vinyl cation intermediates, with the E- and Z-hydrofluorination products forming under kinetic and thermodynamic control, respectively.
Assuntos
Alcinos/química , Boratos/química , Compostos de Vinila/síntese química , Halogenação , Estrutura Molecular , Estereoisomerismo , Compostos de Vinila/químicaRESUMO
The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.
Assuntos
Fumarato de Dimetilo/administração & dosagem , Fumarato de Dimetilo/química , Fator 2 Relacionado a NF-E2/metabolismo , Sulfonas/administração & dosagem , Sulfonas/síntese química , Animais , Células HEK293 , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Ratos , Compostos de Vinila/administração & dosagem , Compostos de Vinila/síntese químicaRESUMO
In nanoimprint lithography (NIL), a pattern is created by mechanical deformation of an imprint resist via embossing with a stamp, where the adhesion behavior during the filling of the imprint stamp and its subsequent detachment may impose some practical challenges. Here we explored thermal and reverse NIL patterning of polyvinylferrocene and vinylferrocene-methyl methacrylate copolymers to prepare complex non-spherical objects and patterns. While neat polyvinylferrocene was found to be unsuitable for NIL, freshly-prepared vinylferrocene-methyl methacrylate copolymers, for which identity and purity were established, have been structured into 3D-micro/nano-patterns using NIL. The cross-, square-, and circle-shaped columnar structures form a 3 × 3 mm arrangement with periodicity of 3 µm, 1 µm, 542 nm, and 506 nm. According to our findings, vinylferrocene-methyl methacrylate copolymers can be imprinted without further additives in NIL processes, which opens the way for redox-responsive 3D-nano/micro-objects and patterns via NIL to be explored in the future.
Assuntos
Compostos Ferrosos/química , Metilmetacrilato/química , Nanocompostos/química , Polímeros/química , Compostos de Vinila/química , Compostos Ferrosos/síntese química , Metilmetacrilato/síntese química , Impressão Molecular , Polímeros/síntese química , Polivinil/síntese química , Polivinil/química , Propriedades de Superfície , Compostos de Vinila/síntese químicaRESUMO
Some 5-substituted ribavirin analogues have a high antiviral and anticancer activity, but their mechanisms of action are obviously not the same as their parent compound. The SAR studies performed on 3 (5)-substituted 1,2,4-triazole nucleosides have shown a high dependency between the structure of the 3 (5)-substituent and the level of antiviral/anticancer activity. The most active substances of the row contain coplanar with the 1,2,4-triazole ring aromatic substituent which is connected by a rigid ethynyl bond. However, the compounds with the trans-vinyl linker also had antiviral activity. We decided to study the antitumor activity of ribavirin analogues with alkyl/aryl vinyl substituents in the 5th position of the 1,2,4-triazole ring. Protected nucleoside analogues with various 5-alkylvinyl substituents were obtained by Horner-Wadsworth-Emmons reaction from the common precursor and converted to the nucleosides. Arylvinyl nucleosides were synthesised according the reported procedures. All compounds did not show significant antiproliferative activity on several tumour cell lines. Coplanar aromatic motif in the 5-substituent for the anticancer activity manifestation was confirmed.
Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Nucleosídeos/farmacologia , Triazóis/farmacologia , Compostos de Vinila/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Hepacivirus/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1-0.4 µM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei (EC50 = 1-15 µM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC50 = 5-8 µM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.
Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Peptidomiméticos/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Compostos de Vinila/farmacologia , Animais , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/metabolismo , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Mioblastos Cardíacos/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/metabolismoRESUMO
Disulfide re-bridging strategy has demonstrated significant advantages in the construction of homogeneous antibody drug conjugates (ADCs). However, a major issue that disulfide scrambling at the hinge region of antibody leads to the formation of "half-antibody" has appeared for many re-bridging linkers. We present bis(vinylsulfonyl)piperazines (BVP) as efficient linkers to selectively re-bridge disulfides at the antigen-binding fragment (Fab) regions and produce highly homogeneous conjugates with a loading of two drugs without disulfide scrambling. We also found that optically active (S)-configuration linkers led to more sufficient conjugation compared with (R)-configuration. The BVP-linked ADCs demonstrated superior efficacy and antigen-selectivity in vitro cytotoxicity.
Assuntos
Imunoconjugados/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Compostos de Vinila/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Dissulfetos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoconjugados/química , Imunoconjugados/toxicidade , Piperazinas/síntese química , Piperazinas/toxicidade , Sulfonas/síntese química , Sulfonas/toxicidade , Compostos de Vinila/síntese química , Compostos de Vinila/toxicidadeRESUMO
The use of conjugated polymer nanoparticles (CP NPs) of poly(9,9-dioctylfluorene-alt-benzothiadiazole) and poly(9,9-di-n-octylfluorenyl-2,7-diyl) as efficient photoinitiator systems (PIS) of vinyl polymerization in water is reported herein. CP NPs are biocompatible, excitable with blue commercial LEDs and, unlike visible light Type II PIS, do not need co-initiators to trigger a monomer chain reaction. CP NPs photoinitiate polymerization of a variety of acrylic monomers with initiation rates comparable to those observed for well-known Type II PIS. Given the extraordinarily large molar absorption coefficients of CP NPs (≈108 m-1 cm-1 ) very low particle concentration is required for effective polymerization. Additionally, CP NPs behave as conventional macrophotoinitiators significantly reducing contamination risks due to leaching of low molecular weight byproducts. These combined features make CP NPs PIS suitable to synthesize polymeric materials for many healthcare and biomedical applications including drug delivery, tissue engineering, prosthetic implants, and food/medicine packaging. These CP NPs PIS are also used to synthesize nano-hydrogels with a relatively narrow and controlled size distribution in the absence of surfactants. It is proposed that polymerization is initiated at the CP NPs surface by photogenerated free polarons, in close analogy to the mechanism previously described for PIS based on inorganic semiconductor NPs.
Assuntos
Luz , Nanopartículas/química , Polímeros/química , Compostos de Vinila/síntese química , Tamanho da Partícula , Polimerização , Solubilidade , Propriedades de Superfície , Compostos de Vinila/química , Água/químicaRESUMO
The Lewis acid-promoted generation of destabilized vinyl cations from ß-hydroxy diazo ketones leads to an energetically favorable 1,2-shift across the alkene followed by an irreversible C-H insertion to give cyclopentenone products. This reaction sequence overcomes typical challenges of counter-ion trapping and rearrangement reversibility of vinyl cations and has been used to study the migratory aptitudes of nonequivalent substituents in an uncommon C(sp2) to C(sp) vinyl cation rearrangement. The migratory aptitude trends were consistent with those observed in other cationic rearrangements; the substituent that can best stabilize a cation more readily migrates. However, density functional theory calculations show that the situation is more complex. Selectivity in the formation of one conformational isomer of the vinyl cation and facial selective migration across the alkene due to an electrostatic interaction between the vinyl cation and the adjacent carbonyl oxygen work in concert to determine which group migrates. This study provides valuable insight into predicting migration preferences when applying this methodology to the synthesis of structurally complex cyclopentenones that are differentially substituted at the α and ß positions.
Assuntos
Compostos de Vinila/síntese química , Cátions/síntese química , Cátions/química , Cetonas/química , Ácidos de Lewis/química , Estrutura Molecular , Compostos de Vinila/químicaRESUMO
Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197⯱â¯19â¯nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.
Assuntos
Descoberta de Drogas , Ácido Palmítico/antagonistas & inibidores , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Compostos de Vinila/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HEK293 , Humanos , Estrutura Molecular , Ácido Palmítico/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Fatores de Transcrição/metabolismo , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
The 4-vinylpyrimidin-2-one nucleoside (T-vinyl) forms a cross-link with the RNA containing uracil at the complementary site at a high reaction rate. To obtain the stable T-vinyl derivative so that its reactivity is protected until it access to the target site, several derivatives were investigated, and the 2-thiopyridinyl- and 2-thiopyrimidinyl T-vinyl derivatives were determined to be good candidates. The 2-thiopyrimidinyl T-vinyl derivative was found to more efficiently cross-link with mRNA albeit having a better stability than the 2-thiopyridinyl T-vinyl derivative. The investigation using the luciferase (Luc) mRNA, the synthetic mRNA and non-cellular translation system revealed that the translation is terminated at the end of the cross-linked duplex between the mRNA and the oligoribonucleotide (ORN). Thus, the 2-thiopyrimidinyl T-vinyl derivative has successfully demonstrated both a good stability and high efficiency for the cross-linking reaction, and expanded its applicability in biological applications.
Assuntos
Reagentes de Ligações Cruzadas/química , Nucleosídeos/química , Oligorribonucleotídeos/química , RNA Mensageiro/química , Compostos de Vinila/química , Reagentes de Ligações Cruzadas/síntese química , Estrutura Molecular , Nucleosídeos/síntese química , Compostos de Vinila/síntese químicaRESUMO
Although radical polymerizations are among the most prevalent methodologies for the synthesis of polymers with diverse compositions and properties, the intrinsic reactivity and selectivity of radical addition challenge the ability to impart control over the polymerization propagation and produce polymers with defined microstructure. Vinylcyclopropanes (VCPs) can be polymerized through radical ring-opening polymerization to produce polymers possessing linear (l) or cyclic (c) repeat units, providing the opportunity to control polymer structure and modify the polymer properties. Herein, we report the first organocatalyzed photoredox radical ring-opening polymerization of a variety of functionalized VCP monomers, where high monomer conversions and spatial and temporal control were achieved to produce poly(VCPs) with predictable molecular weight and low dispersity. Through manipulating polymerization concentration and temperature, tunable l or c content was realized, allowing further investigation of thermal and viscoelastic materials properties associated with these two distinct compositions. Unexpectedly, the photoredox catalysis enables a postpolymerization modification that converts l content into the c content. Combined experimental and computational studies suggested an intramolecular radical cyclization pathway, where cyclopentane and cyclohexane repeat units are likely formed.
Assuntos
Ciclopropanos/química , Compostos de Vinila/química , Catálise , Ciclização , Ciclopropanos/síntese química , Luz , Oxirredução , Polimerização , Compostos de Vinila/síntese químicaRESUMO
Optimized and stringent chemical methods to profile nascent RNA expression are still in demand. Herein, we expand the toolkit for metabolic labeling of RNA through application of inverse electron demand Diels-Alder (IEDDA) chemistry. Structural examination of metabolic enzymes guided the design and synthesis of vinyl-modified nucleosides, which we systematically tested for their ability to be installed through cellular machinery. Further, we tested these nucleosides against a panel of tetrazines to identify those which are able to react with a terminal alkene, but are stable enough for selective conjugation. The selected pairings then facilitated RNA functionalization with biotin and fluorophores. We found that this chemistry not only is amenable to preserving RNA integrity but also endows the ability to both tag and image RNA in cells. These key findings represent a significant advancement in methods to profile the nascent transcriptome using chemical approaches.