RESUMEN
3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.
Asunto(s)
Iminas , Maleimidas , Fosfinas , Succinimidas , Maleimidas/química , Maleimidas/síntesis química , Fosfinas/química , Catálisis , Iminas/química , Succinimidas/química , Estereoisomerismo , Estructura Molecular , IsomerismoRESUMEN
An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound 3ab showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that 3ab could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and apoptosis. Mechanistic studies revealed that compound 3ab inhibited the proliferation of CRC cells via suppressing the AKT/GSK-3ß pathway. In vivo evaluation demonstrated remarkable antitumor effect of 3ab (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate 3ab could be considered as a potential CRC therapy agent for further development.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Indoles , Maleimidas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Maleimidas/química , Maleimidas/síntesis química , Maleimidas/farmacología , Proliferación Celular/efectos de los fármacos , Animales , Relación Estructura-Actividad , Apoptosis/efectos de los fármacos , Estructura Molecular , Ratones , Relación Dosis-Respuesta a Droga , Ratones Desnudos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacosRESUMEN
The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.
Asunto(s)
Ado-Trastuzumab Emtansina , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/química , Trastuzumab/química , Trastuzumab/farmacología , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Maleimidas/química , Maleimidas/síntesis química , Relación Dosis-Respuesta a Droga , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Maitansina/química , Maitansina/farmacología , Maitansina/síntesis química , Maitansina/análogos & derivados , Línea Celular Tumoral , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/síntesis química , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3ß (GSK-3ß) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 µM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3ß-specific inhibitory activity (2, IC50 = 0.0021 µM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3ß-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3ß. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3ß, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.
Asunto(s)
Aminoaciltransferasas , Glucógeno Sintasa Quinasa 3 beta , Imidazoles , Maleimidas , Relación Estructura-Actividad , Maleimidas/química , Maleimidas/farmacología , Maleimidas/síntesis química , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Humanos , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Relación Dosis-Respuesta a DrogaRESUMEN
Carbon-chain dendritic polymers hold unique properties and promising applications. However, synthesizing carbon-chain dendrimers, beyond conjugated ones, remains a challenge. Here, the use of the iterative single unit monomer insertion technique for synthesizing 2.5 generation partial-carbon-chain dendrimers (G2.5) is described, utilizing bismaleimide as the core, a maleimide-trithiocarbonate conjugate as the branching unit, and indene as the spacer unit, following a divergent growth strategy. The optimized conditions for synthesizing the maleimide-trithiocarbonate branching unit are a bismaleimide to trithiocarbonate ratio of 5:1 and a reaction time of 30 min. The structures are verified using 1H nuclear magnetic resonance, gel permeation chromatography, and matrix-assisted laser desorption/ionization-time of flight mass spectra. A four-arm star polymer is then synthesized using the G2.5 as the core. This synthesis of a partial-carbon-chain dendrimer establishes a foundational step toward creating all-carbon-chain ones and may open new application avenues in material science.
Asunto(s)
Carbono , Dendrímeros , Dendrímeros/química , Dendrímeros/síntesis química , Carbono/química , Estructura Molecular , Maleimidas/química , Maleimidas/síntesis química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Polimerizacion , Polímeros/química , Polímeros/síntesis químicaRESUMEN
Multimodality probes appear of great interest for innovative imaging applications in disease diagnosis. Herein, we present a chemical strategy enabling site-specific double-modification and cyclization of a peptide probe exploiting native chemical ligation (NCL) and thiol-maleimide addition. The synthetic strategy is straightforward and of general applicability for the development of double-labeled peptide multimodality probes.
Asunto(s)
Péptidos , Compuestos de Sulfhidrilo , Maleimidas/síntesis química , Maleimidas/químicaRESUMEN
Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.
Asunto(s)
Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Factores Inmunológicos/uso terapéutico , Maleimidas/uso terapéutico , Neoplasias/tratamiento farmacológico , Profármacos/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Masculino , Maleimidas/síntesis química , Maleimidas/farmacología , Ratones Endogámicos BALB C , Ratones SCID , Estructura Molecular , Platino (Metal)/química , Profármacos/síntesis química , Profármacos/farmacología , Relación Estructura-Actividad , Succinimidas/síntesis química , Succinimidas/farmacología , Succinimidas/uso terapéuticoRESUMEN
Self-healing hydrogels with pH-responsiveness could protect loaded drugs from being destroyed till it arrives to the target. The pectin-based hydrogel is a candidate due to the health benefit, anti-inflammation, antineoplastic activity, nontoxicity, and biospecific degradation, et al. However, the abundant existence of water-soluble branched heteropolysaccharide chains influenced its performance resulting in limitation of the potential. In the present study, we prepared a series of self-healing pectin/chitosan hydrogels via the Diels-Alder reaction. Moreover, pectin/chitosan composite hydrogel was prepared as a contrast. By comparison, it can be seen that the Diels-Alder reaction greatly improved the cross-linking density of hydrogels. The self-healing experiments showed excellent self-healing performance. In different swelling mediums, significant transformation in the swelling ratio was shown, indicating well-swelling property, pH- and thermo-responsiveness. The drug loading and release studies presented high loading efficiency and sustained release performance. The cytotoxicity assay that showed a high cell proliferation ratio manifested great cytocompatibility.
Asunto(s)
Quitosano/química , Portadores de Fármacos/química , Hidrogeles/química , Pectinas/química , Animales , Línea Celular , Quitosano/síntesis química , Quitosano/toxicidad , Citrus/química , Reacción de Cicloadición , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Fluorouracilo/química , Furanos/síntesis química , Furanos/química , Furanos/toxicidad , Hidrogeles/síntesis química , Hidrogeles/toxicidad , Concentración de Iones de Hidrógeno , Cinética , Maleimidas/síntesis química , Maleimidas/química , Maleimidas/toxicidad , Fenómenos Mecánicos , Ratones , Pectinas/síntesis química , Pectinas/toxicidad , TemperaturaRESUMEN
A simple and efficient BF3-OEt2 promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was evaluated against HT-29 (Colorectal), Hepg2 (Liver) and A549 (Lung) human cancer cell lines. One of the compounds, 3w, having N,N-Dimethylatedindolylsuccinimide is a potent congener amongst the series with IC50 value 0.02 µM and 0.8 µM against HT-29 and Hepg2 cell lines, respectively, and compound 3i was most active amongst the series with IC50 value 1.5 µM against A549 cells. Molecular docking study and mechanism of reaction have briefly beendiscussed. This method is better than previous reports in view of yield and substrate scope including electron deficient indoles.
Asunto(s)
Antineoplásicos/síntesis química , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Indoles/síntesis química , Maleimidas/síntesis química , Succinimidas/síntesis química , Células A549 , Alquilación , Antineoplásicos/farmacología , Sitios de Unión , Catálisis , Quinasa 2 Dependiente de la Ciclina/química , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Células HT29 , Células Hep G2 , Humanos , Indoles/farmacología , Cinética , Maleimidas/farmacología , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Relación Estructura-Actividad , Especificidad por Sustrato , Succinimidas/farmacologíaRESUMEN
BACKGROUND: Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-ß-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition. METHODS: The compounds (4, 9-11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target. RESULTS: Four Michael adducts (4, 9-11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC50 values of 128 and 65 µM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC50 value of 5.79 µM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions. CONCLUSION: Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.
Asunto(s)
Analgésicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Edema/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/farmacología , Maleimidas/farmacología , Estireno/farmacología , Ácido Acético , Analgésicos/síntesis química , Analgésicos/química , Animales , Araquidonato 5-Lipooxigenasa/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Edema/inducido químicamente , Edema/metabolismo , Femenino , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Masculino , Maleimidas/síntesis química , Maleimidas/química , Ratones , Ratones Endogámicos BALB C , Prostaglandina-Endoperóxido Sintasas/metabolismo , Estireno/síntesis química , Estireno/químicaRESUMEN
Diels-Alder reactions on the surface of nanoparticles allow a thermoreversible functionalization of the nanosized building blocks. We report the synthesis of well-defined magnetite nanoparticles by thermal decomposition reaction and their functionalization with maleimide groups. Attachment of these dienophiles was realized by the synthesis of organophosphonate coupling agents and a partial ligand exchange of the original carboxylic acid groups. The functionalized iron oxide particles allow a covalent surface attachment of a furfuryl-functionalized rhodamine B dye by a Diels-Alder reaction at 60 °C. The resulting particles showed the typical fluorescence of rhodamine B. The dye can be cleaved off the particle surface by a retro-Diels-Alder reaction. The study showed that organic functions can be thermoreversibly attached onto inorganic nanoparticles.
Asunto(s)
Colorantes Fluorescentes/química , Nanopartículas de Magnetita/química , Maleimidas/química , Reacción de Cicloadición , Compuestos Inorgánicos/química , Maleimidas/síntesis química , Rodaminas/química , Propiedades de Superficie/efectos de los fármacosRESUMEN
A new series of pyrrole analogs were developed via the microwave irradiation synthesis. Consequently, got a high yield of the products. As pyrroles are familiar for showing various biological properties, all obtained compounds were screened for their antioxidant properties, most of the compounds showing significant activity. In fact, the motifs 5e, 5g, 5h and 5m showed outstanding antioxidant properties. Further, to enlighten the biologically energetic behavior underlying the antioxidant activity, compounds DFT studies were performed. Noteworthy results have been attained and the structure activity relationship (SAR) was discussed with the support of this results. It was found that highly biological active compounds exhibited a low HOMO-LUMO energy gap (Eg) and the high Eg value compounds show very low/negligible or inactive antioxidant activities. In other cases, compounds containing high HOMO energy levels also provide high antioxidant activity. The thought-provoking point of our results is that theoretical descriptors of the HOMO-LUMO energy gap and the highest occupied molecular orbital energy are important descriptors in the bioorganic research to support the biological experiments.
Asunto(s)
Depuradores de Radicales Libres/química , Maleimidas/química , Teoría Funcional de la Densidad , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/efectos de la radiación , Anhídridos Maleicos/química , Anhídridos Maleicos/efectos de la radiación , Maleimidas/síntesis química , Maleimidas/efectos de la radiación , Microondas , Modelos Químicos , Estructura Molecular , Fenilendiaminas/química , Fenilendiaminas/efectos de la radiación , Relación Estructura-ActividadRESUMEN
Macroporous cryogels that are amenable to facile functionalization are attractive platforms for biomolecular immobilization, a vital step for fabrication of scaffolds necessary for areas like tissue engineering and diagnostic sensing. In this work, thiol-reactive porous cryogels are obtained via photopolymerization of a furan-protected maleimide-containing poly(ethylene glycol) (PEG)-based methacrylate (PEGFuMaMA) monomer. A series of cryogels are prepared using varying amounts of the masked hydrophilic PEGFuMaMA monomer, along with poly(ethylene glycol) methyl ether methacrylate and poly(ethylene glycol) dimethacrylate, a hydrophilic monomer and cross-linker, respectively, in the presence of a photoinitiator. Subsequent activation to the thiol-reactive form of the furan-protected maleimide groups is performed through the retro Diels-Alder reaction. As a demonstration of direct protein immobilization, bovine serum albumin is immobilized onto the cryogels. Furthermore, ligand-directed immobilization of proteins is achieved by first attaching mannose- or biotin-thiol onto the maleimide-containing platforms, followed by ligand-directed immobilization of concanavalin A or streptavidin, respectively. Additionally, we demonstrate that the extent of immobilized proteins can be controlled by varying the amount of thiol-reactive maleimide groups present in the cryogel matrix. Compared to traditional hydrogels, cryogels demonstrate enhanced protein immobilization/detection. Additionally, it is concluded that utilization of a longer linker, distancing the thiol-reactive maleimide group from the gel scaffold, considerably increases protein immobilization. It can be envisioned that the facile fabrication, conjugation, and control over the extent of functionalization of these cryogels will make these materials desirable scaffolds for numerous biomedical applications.
Asunto(s)
Criogeles/química , Proteínas Inmovilizadas/química , Metacrilatos/química , Polietilenglicoles/química , Albúmina Sérica Bovina/química , Materiales Inteligentes/química , Compuestos de Sulfhidrilo/química , Animales , Bovinos , Química Clic , Criogeles/síntesis química , Reacción de Cicloadición , Maleimidas/síntesis química , Maleimidas/química , Metacrilatos/síntesis química , Polietilenglicoles/síntesis química , Porosidad , Materiales Inteligentes/síntesis químicaRESUMEN
A set of new Schiff bases of N-aryl 3- and 4-substituted maleimides has been prepared via condensation of N-aryl 3- and 4- substituted maleimides with p-toluene sulfonyl hydrazide in acidic medium at room temperature. The structures of synthesized compounds were characterized by IR, 1H NMR, 13C NMR, MS spectral data, and further confirmed by single-crystal x-ray crystallography for 5c. The computational study was carried out using Gaussian 09 software by using the B3LYP/6-311+G(d,p) basis set. Single-crystal study results showed much closeness with computational study results. These novel compounds were screened for their antimicrobial activity against two pathogenic bacteria such as Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC25923) and two pathogenic fungi such as Aspergillus niger (MCIM10231) and Candida albicans (MTCC6275). The investigation of antimicrobial screening data showed that the most of tested compounds are moderate to good microbial inhibitors.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Teoría Funcional de la Densidad , Maleimidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Aspergillus niger/efectos de los fármacos , Candida albicans/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Maleimidas/síntesis química , Maleimidas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Bases de Schiff/síntesis química , Bases de Schiff/química , Bases de Schiff/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Maleimide is widely applied in many fields, especially in antibody-drug conjugations and peptide drugs. Herein, we develop a strategy for the C-H alkenylation of tryptophan and tryptophan-containing peptides, providing a synthetic route of decorating maleimide on peptides. The method has a high tolerance of functional groups and protecting groups. Furthermore, this method was applied to prepare peptide conjugation with molecules such as drugs and fluorescence probes. Moreover, macrocyclic peptides were obtained via this reaction.
Asunto(s)
Alquenos/química , Maleimidas/síntesis química , Péptidos/síntesis química , Rodio/química , Triptófano/síntesis química , Catálisis , Maleimidas/química , Estructura Molecular , Péptidos/química , Triptófano/químicaRESUMEN
An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.
Asunto(s)
Antineoplásicos/farmacología , Aziridinas/farmacología , Maleimidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aziridinas/síntesis química , Aziridinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Maleimidas/síntesis química , Maleimidas/química , Estructura MolecularRESUMEN
Two highly selective OFF-ON isomer fluorescent probes (1 and 2) for homo-/cysteine were designed and synthesized. The pyrene modified tetraphenylethylene derivative with AIE was used as luminescent group while maleimide was used as recognition group. These two isomer probes were found to be nearly nonfluorescent when treated with GSH. However, upon interaction with Cys or Hcy, the fluorescence was enhanced by 2000 folds in a wide pH range from 3 to 10. Experimental results and DFT calculation have demonstrated that the fluorescence OFF-ON switch of such thiol probes is resulted from the termination of the PET (photo-induced electron transfer) effect through the Michael addition reaction of maleimide unit and thiols. In addition, probe 1 and 2 exhibit excellent selectivity and sensitivity towards Cys, Hcy over GSH and other amino acids, which was confirmed by mass MS. We suggested that Michael addition reaction of these probes with GSH was prevented because of the stereo-hindrance effect. Furthermore, these two isomer probes were successfully used for imaging biothiols in living H1299 lung cancer cells.
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Cisteína/análisis , Colorantes Fluorescentes/química , Glutatión/química , Homocisteína/análisis , Línea Celular Tumoral , Cisteína/química , Teoría Funcional de la Densidad , Fluorescencia , Colorantes Fluorescentes/síntesis química , Homocisteína/química , Humanos , Maleimidas/síntesis química , Maleimidas/química , Microscopía Fluorescente/métodos , Modelos Químicos , Estilbenos/síntesis química , Estilbenos/químicaRESUMEN
The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-18F-fluoropropane-1-thiol and 2-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (18F-fluoro-PEG4 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate leaving group. The radiofluorination was fully automated on an Eckert & Ziegler synthesis system using standard Kryptofix222/K2CO3 conditions. In order to minimize the amount of biological molecule required for subsequent conjugation, the intermediates, S-(3-18F-fluoropropyl) benzothioate and 18F-fluoro-PEG4 benzothioate, were purified by HPLC. The intermediates were isolated from the HPLC in yields of 37-47% and 28-35%, respectively, and retrieved from eluate using solid phase extraction. Treatment of the benzothioates with sodium methoxide followed by acetic acid provided the free thiols. The desired maleimide substrate in acetonitrile or phosphate buffer was then added and incubated at room temperature for 15â¯min. The final radiolabeled bioconjugate was purified on a separate HPLC or NAP-5 column. Maleimides utilized for the coupling reaction included phenyl maleimide, an Evans Blue maleimide derivative, a dimeric RGDfK maleimide (E[c(RGDfK)]2), two aptamer maleimides, and PSMA maleimide derivative. Isolated radiochemical yields (non-decay corrected) of maleimide addition products based on starting 18F-fluoride ranged from 6 to 22% in a synthesis time of about 90â¯min. 18F-thiol prosthetic groups were further tested in vivo by conjugation to E[c(RGDfK)]2 maleimide in a U87MG xenograft model. PET studies demonstrated similar tumor accumulation of both prosthetic groups. 18F-fluoro-PEG4-S-E[c(RGDfK)]2 displayed a somewhat favorable pharmacokinetics compared to 18F-fluoropropyl-S-E[c(RGDfK)]2. Bone uptake was low for both indicating in vivo stability.
Asunto(s)
Alcanosulfonatos/química , Indicadores y Reactivos/química , Maleimidas/farmacología , Péptidos/farmacología , Radiofármacos/farmacología , Compuestos de Sulfhidrilo/química , Animales , Línea Celular Tumoral , Radioisótopos de Flúor/química , Humanos , Marcaje Isotópico/métodos , Maleimidas/síntesis química , Ratones Desnudos , Péptidos/síntesis química , Radiofármacos/síntesis químicaRESUMEN
Enantioselective catalysis of excited-state photoreactions remains a substantial challenge in synthetic chemistry, and intermolecular photoreactions have proven especially difficult to conduct in a stereocontrolled fashion. Herein, we report a highly enantioselective intermolecular [2 + 2] cycloaddition of 3-alkoxyquinolones catalyzed by a chiral hydrogen-bonding iridium photosensitizer. Enantioselectivities as high as 99% ee were measured in reactions with a range of maleimides and other electron-deficient alkene reaction partners. An array of kinetic, spectroscopic, and computational studies supports a mechanism in which the photocatalyst and quinolone form a hydrogen-bonded complex to control selectivity, yet upon photoexcitation of this complex, energy transfer sensitization of maleimide is preferred. The sensitized maleimide then reacts with the hydrogen-bonded quinolone-photocatalyst complex to afford a highly enantioenriched cycloadduct. This finding contradicts a long-standing tenet of enantioselective photochemistry that held that stereoselective photoreactions require strong preassociation to the sensitized substrate in order to overcome the short lifetimes of electronically excited organic molecules. This system therefore suggests that a broader range of alternate design strategies for asymmetric photocatalysis might be possible.
Asunto(s)
Alquenos/química , Iridio/química , Maleimidas/química , Quinolonas/química , Alcoholes/síntesis química , Alcoholes/química , Alquenos/síntesis química , Catálisis , Reacción de Cicloadición/métodos , Transferencia de Energía , Enlace de Hidrógeno , Maleimidas/síntesis química , Procesos Fotoquímicos , Quinolonas/síntesis química , EstereoisomerismoRESUMEN
Glucagonlike peptide1 (GLP1) and its receptor (GLP1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a noninvasive method for monitoring GLP1R expression. In the present study, a fluorine18labeled aluminum fluoride exendin4 analog [18FAlF conjugated with 1,4,7triazacyclononanetriacetic acid (NOTA)maleimide (MAL)Cys40exendin4] was synthesized and evaluated in a rat MI/R model for GLP1R imaging. NOTAMALCys40exendin4 was synthesized by coupling Cys40exendin4 with NOTAMAL. NOTAMALCys40exendin4 was then conjugated with 18FAlF to obtain 18FAlFNOTAMALCys40exendin4. The yield of 18FAlFNOTAMALCys40exendin4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP1R and an appropriate signaltonoise ratio. At 8 h postMI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) postMI/R compared with 8 h postMI/R, but still remained higher compared with shamoperated groups (0.06±0.012 %ID/g; n=6). Preinjected unlabeled exendin4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18FAlFNOTAMALCys40exendin4 demonstrated favorable characteristics for GLP1R imaging following MI/R. PET imaging using 18FAlFNOTAMALCys40exendin4 in rodent hearts after MI/R revealed a dynamic pattern of GLP1R upregulation.