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1.
Mol Pharm ; 21(11): 5577-5597, 2024 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-39365693

RESUMEN

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo, and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC50/PPT = 0.25-1.77 µM and IC50/PTX = 0.07-0.75 µM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC50 = 4.57 µM; SI = 1.2), free PTX (IC50 = 0.97 µM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.


Asunto(s)
Neoplasias de la Mama , Dextranos , Sinergismo Farmacológico , Nanopartículas , Paclitaxel , Piperidonas , Humanos , Paclitaxel/farmacología , Paclitaxel/química , Dextranos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Nanopartículas/química , Células MCF-7 , Piperidonas/química , Piperidonas/farmacología , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Acetales/química , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química
2.
J Mater Chem B ; 12(42): 10850-10860, 2024 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-39417544

RESUMEN

The abnormal aggregation of Aß proteins, inflammatory responses, and mitochondrial dysfunction have been reported as major targets in Alzheimer's disease (AD). Photooxygenation of the amyloid-ß peptide (Aß) is viewed as a promising therapeutic intervention for AD treatment. However, the limitations of the depth of the external light source passing through the brain and the toxic side effects on healthy tissues are two significant challenges in the photooxidation of Aß aggregates. We proposed a method to initiate the chemical stimulation of Aß1-42 aggregate oxidation through H2O2 and correct the abnormal microenvironment of the lesions by eliminating the cascading reactions of oxidative stress. The degradable G-poly(thioacetal) undergoes cascade release of cinnamaldehyde (CA) and thioacetal triggered by endogenous H2O2, with CA in turn amplifying degradation by generating more H2O2 through mitochondrial dysfunction. A series of novel photosensitizers have been prepared and synthesized for use in the photodynamic oxidation of Aß1-42 aggregates under white light activation. The nanoparticles (BD-6-QM/NPs) self-assembled from BD-6-QM, bis[2,4,5-trichloro-6-(pentoxycarbonyl) phenyl] ester (CPPO), and G-poly(thioacetal) not only exhibit H2O2-stimulated controlled release but also can be chemically triggered by H2O2 to generate singlet oxygen to inhibit Aß1-42 aggregates, reducing the Aß1-42-induced neurotoxicity.


Asunto(s)
Péptidos beta-Amiloides , Fragmentos de Péptidos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Animales , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Acroleína/química , Acroleína/análogos & derivados , Acroleína/farmacología , Agregado de Proteínas/efectos de los fármacos , Humanos , Tamaño de la Partícula , Nanopartículas/química , Acetales/química , Acetales/farmacología , Polímeros/química , Polímeros/farmacología , Procesos Fotoquímicos , Oxidación-Reducción , Ratas , Luz
3.
Nat Commun ; 15(1): 7080, 2024 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-39152141

RESUMEN

C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks. Overall, the 2-3 fold reduction in step-count compares favorably to even recently reported biocatalytic approaches and should ultimately enable new opportunities in drug design around this popular chemotype.


Asunto(s)
Nucleósidos , Nucleósidos/química , Nucleósidos/síntesis química , Estereoisomerismo , Antivirales/síntesis química , Antivirales/química , Acetales/química , Diseño de Fármacos
4.
Carbohydr Res ; 544: 109249, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39191198

RESUMEN

An efficient synthetic strategy has been developed to achieve a pyruvic acid acetal containing tetrasaccharide repeating unit corresponding to the K82 capsular polysaccharide of Acinetobacter baumannii LUH5534 strain in very good yield. The synthetic scheme involves the use of suitably functionalized monosaccharide thioglycosides as glycosyl donors and a combination of N-iodosuccinimide (NIS) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) as thiophilic glycosylation activator to furnish satisfactory yield of the products with appropriate stereochemistry at the glycosidic linkages. Incorporation of the (R)-pyruvic acid acetal in the d-galactose moiety was achieved in very good yield by the treatment of the diol derivative with methyl 2,2-bis(p-methylphenylthio)propionate in the presence of a combination of NIS and triflic acid.


Asunto(s)
Acetales , Acinetobacter baumannii , Oligosacáridos , Polisacáridos Bacterianos , Acinetobacter baumannii/química , Acetales/química , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/síntesis química , Oligosacáridos/química , Oligosacáridos/síntesis química , Ácido Pirúvico/química , Secuencia de Carbohidratos , Cápsulas Bacterianas/química
5.
Chem Biol Drug Des ; 104(1): e14581, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38997237

RESUMEN

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.


Asunto(s)
Antineoplásicos , Etilenos , Compuestos Heterocíclicos , Cetonas , Humanos , Línea Celular Tumoral , Etilenos/química , Etilenos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Relación Estructura-Actividad , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Acetales/química , Acetales/farmacología , Acetales/síntesis química , Proteínas Represoras
6.
Chem Pharm Bull (Tokyo) ; 72(8): 731-746, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39085089

RESUMEN

Nitrones are widely used as 1,3-dipoles in organic synthesis, but control of their reactions is not always easy. This review outlines our efforts to make the reactions of nitrones more predictable and easier to use. These efforts can be categorized into (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.


Asunto(s)
Óxidos de Nitrógeno , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/síntesis química , Reacción de Cicloadición , Estructura Molecular , Acetales/química , Acetales/síntesis química , Cetonas/química , Cetonas/síntesis química , Oximas/química , Oximas/síntesis química , Etilenos/química , Estereoisomerismo
7.
Carbohydr Res ; 541: 109167, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38823063

RESUMEN

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.


Asunto(s)
Glicósidos , Glicósidos/química , Glicósidos/síntesis química , Agua/química , Estereoisomerismo , Cetonas/química , Catálisis , Acetales/química , Estructura Molecular
8.
J Am Chem Soc ; 146(20): 13836-13845, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38717976

RESUMEN

Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.


Asunto(s)
Liberación de Fármacos , Hidrogeles , Hidrogeles/química , Hidrogeles/síntesis química , Animales , Ratones , Acetales/química , Paclitaxel/química , Paclitaxel/farmacocinética , Éteres/química , Polietilenglicoles/química , Polímeros/química , Polímeros/síntesis química , Portadores de Fármacos/química
9.
ACS Appl Bio Mater ; 7(6): 3810-3820, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38795048

RESUMEN

Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.


Asunto(s)
Dextranos , Inflamación , Ensayo de Materiales , Nanopartículas , Tamaño de la Partícula , Dextranos/química , Nanopartículas/química , Inflamación/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Ratones , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Animales , Acetales/química , Humanos , Liberación de Fármacos , Sistemas de Liberación de Medicamentos , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Medicina de Precisión
11.
Angew Chem Int Ed Engl ; 63(19): e202403396, 2024 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-38490953

RESUMEN

Although solid-phase peptide synthesis combining with chemical ligation provides a way to build up customized polypeptides in general, many targets are still presenting challenges for the conventional synthetic process, such as hydrophobic proteins. New methods and strategies are still required to overcome these obstacles. In this study, kinetic studies of Cys/Pen ligation and its acidolysis were performed, from which the fast acidolysis of substituted N,S-benzylidene thioacetals (NBTs) was discovered. The study demonstrates the potential of NBTs as a promising Cys switchable protection, facilitating the chemical synthesis of peptides and proteins by efficiently disrupting peptide aggregation. The compatibility of NBTs with other commonly adopted Cys protecting groups and their applications in sequential disulfide bond formation were also investigated. The first chemical synthesis of the native human programmed death ligand 1 immunoglobulin V-like (PD-L1 IgV) domain was achieved using the NBT strategy, showcasing its potential in difficult protein synthesis.


Asunto(s)
Cisteína , Péptidos , Cisteína/química , Péptidos/química , Péptidos/síntesis química , Humanos , Acetales/química , Compuestos de Bencilideno/química , Compuestos de Bencilideno/síntesis química , Proteínas/química , Proteínas/síntesis química
12.
Macromol Rapid Commun ; 45(12): e2400097, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38499007

RESUMEN

Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery.


Asunto(s)
Acetales , Benzaldehídos , Acetales/química , Benzaldehídos/química , Concentración de Iones de Hidrógeno , Hidrólisis , Polímeros/química , Polímeros/síntesis química , Polietilenglicoles/química , Humanos , Estructura Molecular , Portadores de Fármacos/química , Portadores de Fármacos/síntesis química
13.
Org Lett ; 25(26): 4903-4907, 2023 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-37358405

RESUMEN

After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise a new approach aiming at an improved supply of this scarce marine natural product; this compound is a cometabolite of the prototypical phosphatase inhibitor okadaic acid but still awaits detailed biological profiling. The revised entry starts from 2-deoxy-d-glucose; keys to success were a telescoped hemiacetal reduction/acetal cleavage and an exquisitely selective gold/Brønsted acid-cocatalyzed spiroacetalization.


Asunto(s)
Inhibidores Enzimáticos , Furanos , Ácido Ocadaico/química , Ácido Ocadaico/farmacología , Inhibidores Enzimáticos/química , Acetales/química
14.
Macromol Rapid Commun ; 44(13): e2300099, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37020406

RESUMEN

To cope with the severe plastic waste crisis, massive efforts are made to develop sustainable polymer materials whose degradation involves a disposing and decomposing to small molecule (DDM) and/or a chemical recycling to monomer (CRM) process. Polyacetals, a type of pH-responsive polymers, are degradable under acidic conditions, while highly stable under neutral and basic circumstances. As for their synthesis, the cationic ring-opening polymerization (CROP) of cyclic acetals is an elegant and promising approach, though suffering from fatal side reactions and polymerization-depolymerization equilibrium. Recent development in CRM restimulates the interest in the long-forgotten CROP method due to its inherent depolymerization characteristics. In terms of the end-of-life options, polyacetals are recyclable materials with both DDM and CRM potentials. They not only expand the scope of materials for closed-loop recycling but also help to tune the degradation properties of traditional polyesters and polyolefins. This review aims to discuss the synthesis of various polyacetals by CROP and their degradation properties from the perspectives of 1) polymerization of cyclic acetals, dioxepins, and hemiacetal esters, 2) copolymerization of cyclic acetals with heterocyclic or vinyl monomers, and 3) degradation and recycling properties of the related polymers.


Asunto(s)
Acetales , Polímeros , Polimerizacion , Acetales/química , Polímeros/química , Poliésteres
15.
Biomacromolecules ; 24(2): 991-1002, 2023 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-36724405

RESUMEN

Radical ring-opening polymerization (rROP) of cyclic ketene acetals (CKAs) with traditional vinyl monomers allows the synthesis of degradable vinyl copolymers. However, since the most commonly used CKAs are hydrophobic, most degradable vinyl copolymers reported so far degrade very slowly by hydrolysis under physiological conditions (phosphate-buffered saline, pH 7.4, 37 °C), which can be detrimental for biomedical applications. Herein, to design advanced vinyl copolymers by rROP with high CKA content and enhanced degradation profiles, we reported the copolymerization of 2-methylene-1,3,6-trioxocane (MTC) as a CKA with vinyl ether (VE) or maleimide (MI) derivatives. By performing a point-by-point comparison between the MTC/VE and MTC/MI copolymerization systems, and their counterparts based on 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), we showed negligible impact on the macromolecular characteristics and similar reactivity ratios, suggesting successful substitution of MDO and BMDO by MTC. Interestingly, owing to the hydrophilicity of MTC, the obtained copolymers exhibited a faster hydrolytic degradation under both accelerated and physiological conditions. We then prepared MTC-based glycopolymers, which were formulated into surfactant-free nanoparticles, exhibiting excellent colloidal stability up to 4 months and complete degradation under enzymatic conditions. Importantly, MTC-based glyconanoparticles also showed a similar cytocompatibility toward two healthy cell lines and a much stronger lectin affinity than MDO-based glyconanoparticles.


Asunto(s)
Acetales , Nanopartículas , Hidrólisis , Acetales/química , Polímeros/química , Nanopartículas/química , Interacciones Hidrofóbicas e Hidrofílicas
16.
Chemistry ; 28(61): e202202579, 2022 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-36111794

RESUMEN

Aroyl-S,N-ketene acetals are a novel highly diverse class of aggregation-induced emission fluorogens (AIEgens) with a plethora of interesting properties. An expanded compound library of more than 110 dyes set the stage for the first qualitative control and tuneability of all aspects of their photophysical properties. The interplay of substituents not only allows tuning and prediction of the emission color, but also of the intensity, and quantum yields both in solids and in the aggregated state; these can be rationalized by scrutinizing intermolecular interactions in the crystalline solid state.


Asunto(s)
Acetales , Etilenos , Acetales/química , Etilenos/química , Cetonas/química
17.
Biomacromolecules ; 23(9): 4015-4028, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-35971824

RESUMEN

A small library of degradable polyester-like glycopolymers was successfully prepared by the combination of radical ring-opening copolymerization of 2-methylene-1,3-dioxepane as a cyclic ketene acetal (CKA) with vinyl ether (VE) derivatives and a Pd-catalyzed thioglycoconjugation. The resulting thioglycopolymers were formulated into self-stabilized thioglyconanoparticles, which were stable up to 4 months and were enzymatically degraded. Nanoparticles and their degradation products exhibited a good cytocompatibility on two healthy cell lines. Interactions between thioglyconanoparticles and lectins were investigated and highlighted the presence of both specific carbohydrate/lectin interactions and nonspecific hydrophobic interactions. Fluorescent thioglyconanoparticles were also prepared either by encapsulation of Nile red or by the functionalization of the polymer backbone with rhodamine B. Such nanoparticles were used to prove the cell internalization of the thioglyconanoparticles by lung adenocarcinoma (A549) cells, which underlined the great potential of P(CKA-co-VE) copolymers for biomedical applications.


Asunto(s)
Nanopartículas , Acetales/química , Éteres Cíclicos , Nanopartículas/química , Polimerizacion , Polímeros/química
18.
Chem Biodivers ; 19(7): e202100931, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35674435

RESUMEN

The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 µg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.


Asunto(s)
Acetales , Antifúngicos , Acetales/química , Acetales/farmacología , Antibacterianos/farmacología , Anticonvulsivantes/farmacología , Antidepresivos/química , Antidepresivos/farmacología , Antifúngicos/farmacología , Etilenos , Cetonas
19.
J Am Chem Soc ; 144(2): 1045-1055, 2022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-34985904

RESUMEN

Ni/photoredox catalysis has emerged as a powerful platform for C(sp2)-C(sp3) bond formation. While many of these methods typically employ aryl bromides as the C(sp2) coupling partner, a variety of aliphatic radical sources have been investigated. In principle, these reactions enable access to the same product scaffolds, but it can be hard to discern which method to employ because nonstandardized sets of aryl bromides are used in scope evaluation. Herein, we report a Ni/photoredox-catalyzed (deutero)methylation and alkylation of aryl halides where benzaldehyde di(alkyl) acetals serve as alcohol-derived radical sources. Reaction development, mechanistic studies, and late-stage derivatization of a biologically relevant aryl chloride, fenofibrate, are presented. Then, we describe the integration of data science techniques, including DFT featurization, dimensionality reduction, and hierarchical clustering, to delineate a diverse and succinct collection of aryl bromides that is representative of the chemical space of the substrate class. By superimposing scope examples from published Ni/photoredox methods on this same chemical space, we identify areas of sparse coverage and high versus low average yields, enabling comparisons between prior art and this new method. Additionally, we demonstrate that the systematically selected scope of aryl bromides can be used to quantify population-wide reactivity trends and reveal sources of possible functional group incompatibility with supervised machine learning.


Asunto(s)
Acetales/química , Bromuros/química , Luz , Níquel/química , Benzaldehídos/química , Catálisis , Teoría Funcional de la Densidad , Radicales Libres/química , Metilación
20.
Bioconjug Chem ; 33(2): 369-385, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-35015523

RESUMEN

An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150-200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV-vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The in vitro release studies revealed a controlled release of DOX under acidic conditions and curcumin release in response to the enzyme. The value of the combination index calculated on HepG2 cells was found to be <1, and hence, the drug pair curcumin and DOX acts synergistically for tumor regression. To prove the efficiency of acid-labile linkages and the prodrug strategy for effective cancer therapy, curcumin-derived polymers devoid of sensitive linkages were also prepared. The prodrug stimuli-responsive nanomicelles showed enhanced cell cytotoxicity and tumor penetration capability on HepG2 cells as well as drug-resistant MCF-7 cell lines and no effect on normal NIH/3T3 fibroblasts as compared to the nonresponsive micelles. The results were also supported by in vivo evidence on a hepatocellular carcinoma (HCC)-induced nude mice model. An evident decrease in MMP-2, MMP-9, and α-fetoprotein (AFP), the biomarkers specific to tumor progression, was observed along with metastasis upon treatment with the drug-loaded dual-responsive nanomicelles. These observations corroborated with the SGOT and SGPT data as well as the histoarchitecture of the liver tissue in mice.


Asunto(s)
Carcinoma Hepatocelular , Curcumina , Neoplasias Hepáticas , Nanopartículas , Profármacos , Acetales/química , Animales , Biotina , Curcumina/farmacología , Curcumina/uso terapéutico , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Desnudos , Micelas , Nanopartículas/química , Polietilenglicoles/química , Polímeros/química , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Vitaminas
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