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1.
J Med Chem ; 63(24): 15668-15692, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33325696

RESUMO

A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4ß2 and α3ß4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4ß2/α3ß4 selectivity to the α4ß2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus ß2 side converge in indicating that the limited accommodation capacity of the ß2 pocket, compared to that of the ß4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.


Assuntos
Dioxanos/química , Agonistas Nicotínicos/química , Receptores Nicotínicos/química , Sítios de Ligação , Microscopia Crioeletrônica , Dioxanos/síntese química , Dioxanos/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/metabolismo , Pirrolidinas/química , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
2.
Int J Nanomedicine ; 15: 6373-6383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32904686

RESUMO

Background: The treatment of tendon injuries remains a challenging problem in clinical due to their slow and insufficient natural healing process. Scaffold-based tissue engineering provides a promising strategy to facilitate tendon healing and regeneration. However, many tissue engineering scaffolds have failed due to their poor and unstable mechanical properties. To address this, we fabricated nanofibrous polycaprolactone/methacrylated poly(trimethylene carbonate) (PCL/PTMC-MA) composite scaffolds via electrospinning. Materials and Methods: PTMC-MA was characterized by nuclear magnetic resonance. Fiber morphology of composite scaffolds was evaluated using scanning electron microscopy. The monotonic tensile test was performed for determining the mechanical properties of composite scaffolds. Cell viability and collagen deposition were assessed via PrestoBlue assay and enzyme-linked immunosorbent assay, respectively. Results: These PCL/PTMC-MA composite scaffolds had an increase in mechanical properties as PTMC-MA content increase. After photo-crosslinking, they showed further enhanced mechanical properties including creep resistance, which was superior to pure PCL scaffolds. It is worth noting that photo-crosslinked PCL/PTMC-MA (1:3) composite scaffolds had a Young's modulus of 31.13 ± 1.30 MPa and Max stress at break of 23.80 ± 3.44 MPa that were comparable with the mechanical properties of native tendon (Young's modulus 20-1200 MPa, max stress at break 5-100 MPa). In addition, biological experiments demonstrated that PCL/PTMC-MA composite scaffolds were biocompatible for cell adhesion, proliferation, and differentiation.


Assuntos
Células-Tronco Mesenquimais/citologia , Nanofibras/química , Fotoquímica/métodos , Tecidos Suporte/química , Animais , Adesão Celular , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Dioxanos/química , Teste de Materiais , Camundongos Endogâmicos C57BL , Poliésteres/química , Polímeros/química , Regeneração , Tendões/fisiologia
3.
Eur J Med Chem ; 200: 112419, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32502862

RESUMO

1,4-Benzodioxane has long been a versatile template widely employed to design molecules endowed with diverse bioactivities. Its use spans the last decades of medicinal chemistry until today concerning many strategies of drug discovery, not excluding the most advanced ones. Here, more than fifty benzodioxane-related lead compounds, selected from recent literature, are presented showing the different approaches with which they have been developed. Agonists and antagonists at neuronal nicotinic, α1 adrenergic and serotoninergic receptor subtypes and antitumor and antibacterial agents form the most representative classes, but a variety of other biological targets are addressed by benzodioxane-containing compounds.


Assuntos
Dioxanos/química , Desenho de Fármacos , Animais , Química Farmacêutica/métodos , Humanos
4.
J Med Chem ; 63(11): 5763-5782, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32374602

RESUMO

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved.


Assuntos
Dioxanos/química , Antagonistas Muscarínicos/química , Receptores Muscarínicos/química , Animais , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Simulação de Acoplamento Molecular , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacologia , Estrutura Terciária de Proteína , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade
5.
Chemosphere ; 251: 126381, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443232

RESUMO

In this study, carbon quantum dots (CQDs) were used to decorate a TiO2/g-C3N4 (TCN) film electrode. The morphological, optical, and electrochemical properties of the TiO2/g-C3N4/CQDs nanorod arrays (TCNC NRAs) film were investigated using transmission electron microscopy (TEM), scanning electron microscopy (SEM), UV-vis diffuse reflectance spectroscopy (DRS), photoluminescence (PL), and electrochemical impedance spectroscopy (EIS). The improved optical properties, photoelectrochemical properties and photoelectrocatalytic (PEC) performance of photoanode can be observed by doping CQDs onto the TCN NRAs film. Compared with TiO2 NRAs and TCN NRAs, the narrower band gap of 2.47 eV and longer lifetime of photoinduced electron-hole pairs were observed in the TCNC NRAs. Under visible light irradiation and a bias voltage of 1.2 V, the photocurrent density and 1,4-dioxane (1,4-D) removal rate of PEC process with TCNC NRAs electrode reached 0.16 mA/cm2 and 77.9%, respectively, which was 2.5 times and 1.5 times of that with TCN NRAs electrode. TCNC NRAs electrode could keep >75% of the 1,4-D removal rate during five cycles tests. High PEC performance with TCNC NRAs electrode could be attributed to the enhanced charge separation and the change of electron transfer mechanism from typical heterojunction to Z-scheme, which may increase the active species production and change the dominant reactive species from O2·- to ·OH. Our experimental results should be useful for studying the degradation of 1,4-D and developing efficient PEC materials.


Assuntos
Dioxanos/química , Pontos Quânticos/química , Carbono , Eletrodos , Luz , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanotubos/química , Titânio
6.
Eur J Med Chem ; 193: 112218, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208223

RESUMO

Cathepsin X is a cysteine carboxypeptidase that is involved in various physiological and pathological processes. In particular, highly elevated expression and activity of cathepsin X has been observed in cancers and neurodegenerative diseases. Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against cathepsin X compared to Z9, with IC50 values of 7.1 µM-13.6 µM. Additionally, 25 inhibited prostate cancer cell migration by 21%, which is under the control of cathepsin X.


Assuntos
Antineoplásicos/farmacologia , Carboxipeptidases/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Dioxanos/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carboxipeptidases/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Dioxanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Células PC-3 , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais Cultivadas
7.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041130

RESUMO

The reactions of the PMe3 adduct of the silylated germylene [(Me3Si)3Si]2Ge: with GeCl2·dioxane were found to yield 1,1-migratory insertion products of GeCl2 into one or two Ge-Si bonds. In a related reaction, a germylene was inserted with tris(trimethylsilyl)silyl and vinyl substituents into a Ge-Cl bond of GeCl2. This was followed by intramolecular trimethylsilyl chloride elimination to another cyclic germylene PMe3 adduct. The reaction of the GeCl2 mono-insertion product (Me3Si)3SiGe:GeCl2Si(SiMe3)3 with Me3SiC≡CH gave a mixture of alkyne mono- and diinsertion products. While the reaction of a divinylgermylene with GeCl2·dioxane only results in the exchange of the dioxane of GeCl2 against the divinylgermylene as base, the reaction of [(Me3Si)3Si]2Ge: with one GeCl2·dioxane and three phenylacetylenes gives a trivinylated germane with a chlorogermylene attached to one of the vinyl units.


Assuntos
Complexos de Coordenação/síntese química , Dioxanos/química , Fosfinas/química , Complexos de Coordenação/química , Estrutura Molecular , Silanos
8.
Pharmacol Rep ; 72(2): 427-434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32002826

RESUMO

BACKGROUND: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). METHODS: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. RESULTS: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a µM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. CONCLUSIONS: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.


Assuntos
Dioxanos/farmacologia , Descoberta de Drogas , Receptor 5-HT1A de Serotonina/metabolismo , Compostos de Espiro/farmacologia , Animais , Ligação Competitiva , Células CHO , Cricetulus , Dioxanos/química , Dioxanos/metabolismo , Humanos , Ligantes , Estrutura Molecular , Ligação Proteica , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/genética , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
9.
Molecules ; 25(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069968

RESUMO

Ring cleavage of cyclic ether substituents attached to a boron cage via an oxonium oxygen atom are amongst the most versatile methods for conjoining boron closo-cages with organic functional groups. Here we focus on much less tackled chemistry of the 11-vertex zwitterionic compound [10-(O-(CH2-CH2)2O)-nido-7,8-C2B9H11] (1), which is the only known representative of cyclic ether substitution at nido-cages, and explore the scope for the use of this zwitterion 1 in reactions with various types of nucleophiles including bifunctional ones. Most of the nitrogen, oxygen, halogen, and sulphur nucleophiles studied react via nucleophilic substitution at the C1 atom of the dioxane ring, followed by its cleavage that produces six atom chain between the cage and the respective organic moiety. We also report the differences in reactivity of this nido-cage system with the simplest oxygen nucleophile, i.e., OH-. With compound 1, reaction proceeds in two possible directions, either via typical ring cleavage, or by replacement of the whole dioxane ring with -OH at higher temperatures. Furthermore, an easy deprotonation of the hydrogen bridge in 1 was observed that proceeds even in diluted aqueous KOH. We believe this knowledge can be further applied in the design of functional molecules, materials, and drugs.


Assuntos
Boranos/química , Dioxanos/química , Halogênios/química , Boro/química , Nitrogênio/química , Temperatura
10.
Biomater Sci ; 8(7): 2018-2030, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32080689

RESUMO

Poly(l-lactic acid) (PLLA) is a biocompatible and biodegradable polymer that has received much attention as a biomedical material. However, PLLA also produces by-products that acidify the surrounding tissues during in vivo degradation, which induces inflammatory responses. To overcome these problems, magnesium hydroxide nanoparticles (nano-magnesium hydroxide; nMH) were added to the PLLA matrix as a bioactive filler that can suppress inflammatory responses by neutralizing the acidified environment caused by the degradation of PLLA. Despite the advantages of nMH, the strong cohesion of these nanoparticles toward each other makes it difficult to manufacture a polymer matrix containing homogeneous nanoparticles through thermal processing. Here, we prepared two types of surface-modified nMH with oligolactide (ODLLA) utilizing grafting to (GT) and grafting from (GF) strategies to improve the mechanical and biological characteristics of the organic-inorganic hybrid composite. The incorporation of surface-modified nMH not only enhanced mechanical properties, such as Young's modulus, but also improved homogeneity of magnesium hydroxide particles in the PLLA matrix due to the increase in interfacial interaction. Additionally, the PLLA composites with surface-modified nMH exhibited reduced bulk erosion during hydrolytic degradation with lower cytotoxicity and immunogenicity. Hemocompatibility tests on the PLLA composites with nMH showed a higher albumin to fibrinogen ratio (AFR) and a lower influence of platelet activation, when compared with unmodified control samples. Taken all together, the surface-modified nMH could be seen to successfully improve the physical and biological characteristics of polymer composites. We believe this technology has great potential for the development of hybrid nanocomposites for biomedical devices, including cardiovascular implants.


Assuntos
Dioxanos/química , Hidróxido de Magnésio/farmacologia , Poliésteres/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Módulo de Elasticidade , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Hidróxido de Magnésio/química , Teste de Materiais , Nanopartículas , Polímeros/química , Propriedades de Superfície
11.
Biomater Sci ; 8(6): 1683-1694, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-31984995

RESUMO

A major challenge in orthopedics is the repair of large non-union bone fractures. A promising therapy for this indication is the use of biodegradable bioinspired biomaterials that stabilize the fracture site, relieve pain and initiate bone formation and healing. This study uses a multidisciplinary evaluation strategy to assess immunogenicity, allergenicity, bone responses and physicochemical properties of a novel biomaterial scaffold. Two-photon stereolithography generated personalized custom-built scaffolds with a repeating 3D structure of Schwarz Primitive minimal surface unit cell with a specific pore size of ∼400 µm from three different methacrylated poly(d,l-lactide-co-ε-caprolactone) copolymers with lactide to caprolactone monomer ratios of 16 : 4, 18 : 2 and 9 : 1. Using in vitro and in vivo assays for bone responses, immunological reactions and degradation dynamics, we found that copolymer composition influenced the scaffold physicochemical and biological properties. The scaffolds with the fastest degradation rate correlated with adverse cellular effects and mechanical stiffness correlated with in vitro osteoblast mineralization. The physicochemical properties also correlated with in vivo bone healing and immune responses. Overall these observations provide compelling support for these scaffolds for bone repair and illustrate the effectiveness of a promising multidisciplinary strategy with great potential for the preclinical evaluation of biomaterials.


Assuntos
Materiais Biomiméticos/farmacologia , Fraturas não Consolidadas/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos , Animais , Materiais Biomiméticos/química , Caproatos/química , Células Cultivadas , Dioxanos/química , Modelos Animais de Doenças , Feminino , Lactonas/química , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Cultura Primária de Células , Estereolitografia , Engenharia Tecidual
12.
J Agric Food Chem ; 68(7): 2124-2131, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31985223

RESUMO

Lignin acylated with acetate and/or p-coumarate is common in many herbaceous plants. Herein, the biomimetic oxidation of γ-acylated monolignols with Ag2O was studied to understand the effect of γ-acyl groups on monolignol polymerization. The oxidation of sinapyl acetate gave γ-acylated and α-acylated ß-O-4 dimers in 71 and 9.5% yields, respectively. The oxidation of sinapyl p-coumarate produced γ-acylated ß-O-4 and γ-acylated tetralin ß-ß dimers in 53 and 16% yields, respectively. Only the sinapyl alcohol moiety in sinapyl p-coumarate reacted, and the p-coumarate moiety remained unchanged, suggesting that p-coumaric acid is not incorporated into the lignin backbone in the acylated lignins. All of the γ-acylated monolignols used in this study produced the γ-acylated ß-O-4 dimers, which suggests that the γ-acylated monolignols act as lignin monomers. The relatively high yields of the ß-O-4 dimers indicate that Ag2O oxidation of the monolignols can be used as an easy method for synthesizing the ß-O-4 dimer model compounds.


Assuntos
Ácidos Cumáricos/química , Dioxanos/química , Lignina/química , Óxidos/química , Compostos de Prata/química , Acetatos/química , Biomimética , Oxirredução
13.
Vet Surg ; 49(3): 550-560, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31599002

RESUMO

OBJECTIVE: To compare tensile properties of synthetic, absorbable, monofilament suture material before and after incubation in phosphate-buffered saline (PBS). STUDY DESIGN: Two sizes (2-0 and 3-0) of Biosyn, Maxon, Monocryl, PDS II, Securocryl, and Securodox were tested. SAMPLE POPULATION: Ten suture loops per group. METHODS: Tensile strength, elongation, and modulus of suture loops were measured at baseline and after 7, 14, 21, or 28 days of incubation in PBS. RESULTS: Size, suture material, and size × suture material interaction influenced maximum breaking load, maximum elongation, and modulus of elasticity. At baseline, 2-0 and 3-0 Maxon had the highest breaking loads (111.67 N and 79.71 N, respectively) for their size, and 2-0 PDSII and 3-0 Securodox had the lowest (68.71 N and 48.73 N, respectively). Maxon 2-0 and 3-0 had the greatest elongations (9.68 mm and 8.45 mm, respectively) for their size, and 2-0 Biosyn and 3-0 Securocryl had the least (7.21 mm and 6.58 mm, respectively). Biosyn 2-0 and 3-0 had the highest modulus. With incubation, Maxon (2-0), PDS II (2-0, 3-0), and Securodox (2-0, 3-0) maintained or gained strength over 4 weeks. Strengths of 2-0 and 3-0 Biosyn and 3-0 Maxon were maintained for 2 weeks, while Monocryl and Securocryl lost 20% to 44% of baseline strength within 1 week and 60% to 72% within 2 weeks. Day 7 strengths of 2-0 Biosyn and 2-0 Monocryl were greater than baseline strength of 2-0 PDS II. Strength of 3-0 Biosyn at day 14 was greater than strength of Monocryl at days 7 and 14 and greater than strength of 3-0 PDS II, 3-0 Securodox, and 3-0 Securocryl at baseline and days 7 and 14. CONCLUSION: Suture tensile properties varied with suture size, composition, and brand. At baseline, Maxon suture had the greatest strength and elongation, and Biosyn had the greatest stiffness. CLINICAL SIGNIFICANCE: Tensile strength retention, when reported as a percentage of original strength, provides insufficient information for comparison of suture tensile properties.


Assuntos
Dioxanos/química , Teste de Materiais , Polidioxanona/química , Poliésteres/química , Polímeros/síntese química , Suturas , Resistência à Tração , Animais , Tampões (Química) , Fosfatos , Polímeros/química
14.
Mater Sci Eng C Mater Biol Appl ; 106: 110178, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753413

RESUMO

The present work details the fabrication of electrospun tubular scaffolds based on the biocompatible and unexploited blend of gelatin and polytrimethylene carbonate (PTMC) as a media (middle layer of blood vessel) equivalent for blood vessel regeneration. An attempt to resemble the media stimulated the selection of gelatin as a matrix (substitution for collagen) with the inclusion of the biodegradable elastomer PTMC (substitution for elastin). -The work highlights the variation of electrospinning parameters and its assiduous selection based on fiber diameter distribution and pore size distribution to obtain smooth microfibers and micropores which is reported for the first time for this blend. Electrospun conduits of gelatin-PTMC blend had fibers sized 6-8 µm and pores sized ~100-150 µm. Young's modulus of 0.40 ±â€¯0.045 MPa was observed, resembling the tunica media of the native artery (~0.5 MPa). An evaluation of the surface properties, topography, and mechanical properties validated its physical requirements for inclusion in a vascular graft. Preliminary biological tests confirmed its minimal in-vitro toxicity and in-vivo biocompatibility. MTT assay (indirect) elucidated cell viability above 70% with scaffold extract, considered to be non-toxic according to the EN ISO-10993-5/12 protocol. The in-vivo subcutaneous implantation in rat showed a marked reduction in macrophages within 15 days revealing its biocompatibility and its possibility for host integration. This comprehensive study presents for the first time the potential of microporous electrospun gelatin and PTMC blend based tubular construct as a potential biomaterial for vascular tissue engineering. The proposed media equivalent included in a bilayer or trilayer polymeric construct can be a promising off-shelf vascular graft.


Assuntos
Materiais Biocompatíveis/química , Dioxanos/química , Gelatina/química , Polímeros/química , Resistência à Tração , Engenharia Tecidual/métodos , Tecidos Suporte/química
15.
Molecules ; 24(22)2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31744244

RESUMO

Biodegradable polyesters gain significant attention because of their wide potential biomedical applications. The ring-opening polymerization method is widely used to obtain such polymers, due to high yields and advantageous properties of the obtained material. The preparation of new, effective, and bio-safe catalytic systems for the synthesis of biomedical polymers is one of the main directions of the research in modern medical chemistry. The new diethylzinc/propyl gallate catalytic system was first used in the copolymerization of ε-caprolactone and rac-lactide. In this paper, the activity of the new zinc-based catalytic system in the copolymerization of cyclic esters depending on the reaction conditions was described. The microstructure analysis of the obtained copolyesters and their toxicity studies were performed. Resulted copolyesters were characterized by low toxicity, moderate dispersity (1.19-1.71), varying randomness degree (0.18-0.83), and average molar mass (5300-9800 Da).


Assuntos
Caproatos/química , Dioxanos/química , Lactonas/química , Compostos Organometálicos/química , Galato de Propila/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Peso Molecular , Polimerização , Polímeros/química
16.
Molecules ; 24(22)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739538

RESUMO

Ring-opening polymerization (ROP) of cyclic esters (lactones, lactides, cyclic carbonates and phosphates) is an effective tool to synthesize biocompatible and biodegradable polymers. Metal complexes effectively catalyze ROP, a remarkable diversity of the ROP mechanisms prompted the use of density functional theory (DFT) methods for simulation and visualization of the ROP pathways. Optimization of the molecular structures of the key reaction intermediates and transition states has allowed to explain the values of catalytic activities and stereocontrol events. DFT computation data sets might be viewed as a sound basis for the design of novel ROP catalysts and cyclic substrates, for the creation of new types of homo- and copolymers with promising properties. In this review, we summarized the results of DFT modeling of coordination ROP of cyclic esters. The importance to understand the difference between initiation and propagation stages, to consider the possibility of polymer-catalyst coordination, to figure out the key transition states, and other aspects of DFT simulation and visualization of ROP have been also discussed in our review.


Assuntos
Dioxanos/química , Ésteres/química , Lactonas/química , Polimerização
17.
Macromol Rapid Commun ; 40(20): e1900306, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31506988

RESUMO

Commercially available strontium isopropoxide represents a suitable catalyst/initiator for the ring-opening polymerization (ROP) of lactide (LA), ε-caprolactone, δ-valerolactone, δ-caprolactone, and δ-decalactone. Well-defined polyesters are accessible via the solution polymerization of lactide in toluene with a [LA]:[Sr] ratio of 100:1 at room temperature with or without the addition of dodecanol as coinitiator. Kinetic studies and detailed analysis by means of matrix-assisted laser desorption ionization mass spectrometry reveal pseudo-first-order kinetics of the ROP as well as excellent endgroup fidelity of the polylactide (PLA) with isopropyl and dodecyl α-endgroups. Both isopropanolate moieties as well as the coinitiator each initiate PLA chains, enabling the synthesis of PLA with tailored molar mass. The polymerization of ε-caprolactone and δ-valerolactone confirms the high catalyst activity, which causes quantitative monomer conversion after 1 min polymerization time but broad molar mass distributions. In contrast, the catalyst is well suited for the ROP of the less reactive δ-caprolactone and δ-decalactone. Although kinetic studies reveal initially bimodal molar mass distributions, polyesters with dispersity values Ð < 1.2 and unimodal molar mass distributions can be obtained at moderate to high monomer conversions.


Assuntos
Dioxanos/química , Lactonas/química , Óxidos/química , Polimerização , Estrôncio/química , Catálise , Dioxanos/síntese química , Cinética , Lactonas/síntese química , Poliésteres/síntese química , Poliésteres/química
18.
Chem Pharm Bull (Tokyo) ; 67(9): 959-965, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474736

RESUMO

Fibrillated aggregation of amyloid ß (Aß) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aß is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aß fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aß complex in the hydrophobic solution composed of dioxane and water molecules. The Aß conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aß peptides. The conformation was also compared between the calculations with the 42-mer (Aß42) and 40-mer (Aß40) peptides. The simulations for Aß42 demonstrated that Aß peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aß peptides were closely packed in the aqueous solution, and the motions of Aß peptides were suppressed significantly. The N-terminal polar domains of Aß peptides tended to be positioned at the inside of the Aß complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aß peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aß complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aß40 peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aß42 in the structure of the Aß complex, while the C-terminal outward expansion was not so distinct as Aß42 peptides.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Dioxanos/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Água/química
19.
Drug Des Devel Ther ; 13: 2393-2404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409973

RESUMO

Purpose: To evaluate the antihepatotoxic activity of dihydropyrimidinone derivative linked with 1,4-benzodioxane. Methods: A series of novel dihydropyrimidinone derivatives linked with 1,4-benzodioxane moiety were synthesized in good yield. Modern spectroscopic techniques and elemental analysis were used for the identification of the synthesized compounds. The hepatoprotective properties of compound 2, 4-(4-nitrophenyl)-5-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-3,4-dihydropyrimidin-2(1H)-one, was evaluated in a carbon tetrachloride (CCl4)-induced hepatotoxicity rat model. Results: Administration of compound 2 prior to CCl4 exposure produced a dose-dependent decrease in the levels of elevated biochemical parameters compared with the standard drug silymarin. CCl4 induced oxidative stress, increased lipid profile, and decreased high-density lipoprotein (HDL) levels. Compound 2 (20 mg/kg) significantly reduced the lipid profile and significantly improved HDL levels in a dose-dependent manner. CCl4 treatment increased malondialdehyde (MDA) level and decreased nonprotein thiol (NP-SH) and total protein (TP) in liver tissues. Pretreatment of rats with compound 2 (20 mg/kg) decreased MDA level and increased NP-SH and TP in liver tissues. Histopathological examination of liver tissues also confirmed the hepatoprotective activity of compound 2. Conclusion: These results demonstrate the antihepatotoxic activity of compound 2 in CCl4-induced hepatotoxicity model.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Dioxanos/farmacologia , Substâncias Protetoras/farmacologia , Pirimidinonas/farmacologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dioxanos/administração & dosagem , Dioxanos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
20.
J Phys Chem B ; 123(37): 7869-7884, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31452375

RESUMO

1,4-Dioxane is a cytotoxic B2-type human carcinogen, a serious water pollutant produced solely by industrial activity. The effect of 1,4-dioxane on phospholipid membrane models composed of dipalmitoyl-phosphatidylcholine (DPPC) and its branched isomer (isodipalmitoyl-phosphatidylcholine, IPPC) was investigated using MD simulations. Clear and polluted membranes were compared by membrane parameters such as area per lipid (APL), volume per lipid (VPL), compressibility modulus, membrane thickness, and orderliness of lipid tails. While neat systems significantly differ from each other, the presence of the pollutant has the same effect on both types of lipid membranes. High density of dioxane appears in the vicinity of ester groups, which pushes away lipid headgroups from each other, leading to an overall change in lipid structure: APL and VPL grows, while the orderliness of lipid tails, membrane thickness, and compressibility modulus decrease. Orientational preferences of water and dioxane molecules were also investigated and different membrane regions have been specified according to the stance of water molecules. Free-energy profile for 1,4-dioxane penetration mechanism into DPPC membranes was carried out using metadynamics for two different concentrations of the pollutant (c1 = 7.51 g/dm3, c2 = 75.10 g/dm3), which showed that the higher the concentration is, the lower the free energy of penetration gets. Only a small free-energy barrier was found in the headgroup region and accumulation of dioxane is thermodynamically unfavored in the middle of the bilayer. The penetration mechanism has been described in detail based on the orientational preference of 1,4-dioxane molecules and the free-energy profiles.


Assuntos
Dioxanos/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Fosfolipídeos/química , Termodinâmica
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