3,568 research outputs found
Synthesis and Biological Evaluation of Chalcone Scaffolds as Potential Antiangiogenic Agents.
Angiogenesis is an integral part of tumour growth and development. Endothelial cell proliferation, migration and differentiation are the main hallmarks of this physiological process. From this, the use of antiangiogenic therapy have brought about a range of licensed FDA approved agents (that are also used by the NHS), that aim to regress tumour induced angiogenesis. However, issues such as: drug resistance, evasion and poor efficacy have limited the use of antiangiogenic therapy as a main stake in anti-cancer therapy. The need for multi-targeted or combinatorial therapies are ever more needed to enhance the current use of these drugs. Therefore, in an attempt to identify novel compounds that exhibit antiangiogenic activity, a group of 1-3-diphenylpropenones (chalcones) were designed, synthesised and biologically evaluated using AH1 (2-chloro-2’5’-dihydroxychalcone) as the parent compound. Methods: Chalcones were synthesised using variations of the Clasien-Schmidt condensation reaction, to develop a compound library based on AH1 (the parent compound). Thereafter, using HUVECs as an angiogenesis model, the effects of the compounds on HUVEC proliferation and migration were evaluated. This was carried out using the MTT cell proliferation assay and the wound healing “scratch” assay. Therein mechanistic evaluation was carried via gel electrophoresis and chemiluminescence western blot. Main findings: Structure activity relationships (SARs) studies identified, that novel compounds AH9 (2-bromo-2’5’-dihydroxychalcone) and AH12 (2-nitro-2’5’-dihydroxychalcone) were shown to exhibit strong anti-proliferative activity along with AH1. Other synthesised derivatives containing different functional groups such as, alkoxy, halogen and methyl did not exhibit similar activities to AH1. The culmination of structure activity relationship suggested that 2’5’-dihydroxy moiety was important to the observed activity only in conjunction with 2-chloro or now 2-bromo substitution on the other phenyl ring. Due to AH9’s better drug likeness over AH12, AH9 and AH1 were taken forward as the lead candidates. Anti-migratory analysis of lead candidates and licensed drug Sorafenib were conducted against HUVECs. AH9 (p < 0.0007) was shown to exhibit significantly more potent inhibitory effects on endothelial migration than AH1 (p = 0.19) and Sorafenib (p = 0.41) over the 8 hour time course study when compared to the untreated control. Mechanistic evaluation identified that AH9 could be exerting its anti-proliferative and potent anti-migratory activity via inhibiting ERK kinase phosphorylation, this was seen at 10μM (p < 0.0001). Discussion and conclusion: To summarise, anti-proliferative and potent anti-migratory activity, towards HUVECs, of a
novel molecule AH9 have been identified showing significant effects against two hallmarks of the angiogenesis cascade. AH9 presents a strong case as an agent capable of being developed as an angiogenesis inhibitor for anti-angiogenic therapy
Synthesis and Biological Evaluation of Chalcone Scaffolds as Potential Antiangiogenic Agents.
Angiogenesis is an integral part of tumour growth and development. Endothelial cell proliferation, migration and differentiation are the main hallmarks of this physiological process. From this, the use of antiangiogenic therapy have brought about a range of licensed FDA approved agents (that are also used by the NHS), that aim to regress tumour induced angiogenesis. However, issues such as: drug resistance, evasion and poor efficacy have limited the use of antiangiogenic therapy as a main stake in anti-cancer therapy. The need for multi-targeted or combinatorial therapies are ever more needed to enhance the current use of these drugs. Therefore, in an attempt to identify novel compounds that exhibit antiangiogenic activity, a group of 1-3-diphenylpropenones (chalcones) were designed, synthesised and biologically evaluated using AH1 (2-chloro-2’5’-dihydroxychalcone) as the parent compound. Methods: Chalcones were synthesised using variations of the Clasien-Schmidt condensation reaction, to develop a compound library based on AH1 (the parent compound). Thereafter, using HUVECs as an angiogenesis model, the effects of the compounds on HUVEC proliferation and migration were evaluated. This was carried out using the MTT cell proliferation assay and the wound healing “scratch” assay. Therein mechanistic evaluation was carried via gel electrophoresis and chemiluminescence western blot. Main findings: Structure activity relationships (SARs) studies identified, that novel compounds AH9 (2-bromo-2’5’-dihydroxychalcone) and AH12 (2-nitro-2’5’-dihydroxychalcone) were shown to exhibit strong anti-proliferative activity along with AH1. Other synthesised derivatives containing different functional groups such as, alkoxy, halogen and methyl did not exhibit similar activities to AH1. The culmination of structure activity relationship suggested that 2’5’-dihydroxy moiety was important to the observed activity only in conjunction with 2-chloro or now 2-bromo substitution on the other phenyl ring. Due to AH9’s better drug likeness over AH12, AH9 and AH1 were taken forward as the lead candidates. Anti-migratory analysis of lead candidates and licensed drug Sorafenib were conducted against HUVECs. AH9 (p < 0.0007) was shown to exhibit significantly more potent inhibitory effects on endothelial migration than AH1 (p = 0.19) and Sorafenib (p = 0.41) over the 8 hour time course study when compared to the untreated control. Mechanistic evaluation identified that AH9 could be exerting its anti-proliferative and potent anti-migratory activity via inhibiting ERK kinase phosphorylation, this was seen at 10μM (p < 0.0001). Discussion and conclusion: To summarise, anti-proliferative and potent anti-migratory activity, towards HUVECs, of a
novel molecule AH9 have been identified showing significant effects against two hallmarks of the angiogenesis cascade. AH9 presents a strong case as an agent capable of being developed as an angiogenesis inhibitor for anti-angiogenic therapy
Rationalize the synthesis of zeolite catalysts by understanding reaction mechanism
[EN] The present thesis focuses on the rationalization of the zeolite synthesis for
catalysis by understanding the nature of active sites and their microenvironments,
together with their influence on the mechanisms of catalyzed reactions.
In the first part of the thesis, efforts have been put on attempting to achieve the
regioselective locating of active sites in zeolite catalyst and, more specifically, on
tunning acid site locations in zeolite framework. The development of a zeolite
synthesis strategy and an indicator that can describe the aluminum distribution
in the zeolite framework is important to evaluate if the final objective has been
achieved. In this part, in order to evaluate aluminum distribution in MFI
framework, an indicator based on monomolecular and bimolecular mechanisms
of n-hexene catalytic cracking was proposed. First, several ZSM-5 samples were
synthesized, which have been reported in the literature to have different
aluminum distributions. These samples were characterized to be analogous in
physicochemical properties and, then, tested in the n-hexene cracking to justify
the usefulness of the indicator proposed in this work. Using 27Al MAS NMR,
the aluminum locations were proved to be different, which was also reflected by
the indicator in this thesis, justifying its applicability to evaluate aluminum
locations. Afterward, this indicator has been employed to check the zeolite
synthesis methodology that could potentially lead to different aluminum
distribution in zeolite frameworks. Then, a boron-assisted synthesis is proposed
considering that boron and aluminum may have competitive positioning in
ZSM-5 framework. Then, and by means of DFT calculations, we have studied
if the unit cell of MFI shows different stabilities when substituted by aluminum
and/or boron in different T positions. It has been found that boron location is
less favored when introduced in 10-ring channels of the MFI framework, while
aluminum shows no preference for positioning among all the T-sites. ZSM-5
samples with different Si/Al and Si/B were synthesized and their
physicochemical properties as well as the relative proportion of paired and
isolated states of aluminum was characterized. Characterization includes n-hexene cracking, for which the samples showed different preference toward
monomolecular and bimolecular reactions. Finally, once the materials were
proved to have different aluminum distribution, they were employed in
methanol-to-propene (MTP) reactions to show the influence of aluminum
distribution on an industry-relevant reaction where the spatial confinement has
an important impact. Indeed, the samples with aluminum preferentially
positioned in 10-ring channel favored more monomolecular cracking and less
bimolecular side reactions such as oligomerization and hydrogen transfer, giving
higher propene yield and lower amount of alkanes and aromatics.
The second part of the thesis focuses on rationalizing the synthesis of zeolites
with cavities for catalyzing “a priory” selected reaction. More specifically, zeolite
synthesis was carried out using OSDAs that mimic the transition state (TS) or a
relevant intermediate in the target reaction. Ethylbenzene production by
transalkylation between diethylbenzene and benzene was selected as the reaction
to be catalyzed. A potential reaction TS was established and a
diaryldimethylphosphonium OSDA was synthesized that mimicks the transition
state in the diaryl-mediated mechanism of transalkylation between benzene and
diethylbenzene. Then, the OSDA successfully led to the formation of the largepore zeolite ITQ-27. This ITQ-27 was tested in the reaction of transalkylation
between benzene and diethylbenzene. The catalytic performance of this material
was benchmarked to be superior than other commercially employed zeolites,
such as USY, mordenite or Beta with similar physicochemical properties.
Finally, Methanol to olefins (MTO) reaction was chosen as another target
catalytic system, where the reaction pathways are more complicated than
transalkylation between benzene and diethylbenzene but nevertheless they have
been well established in the literature. Thus, several OSDAs were synthesized
mimicking the intermediates and transition states of the paring pathway, which
produces more propene and butenes, which are highly demanded among all
products. The OSDAs led to formation of several cage-based small pore zeolites,
such as CHA, RTH and AEI. All the zeolites obtained were tested in MTO
reactions to evaluate their catalytic activity and gave high selectivity toward light
olefins, which appeared to selectively depend on the zeolite tested. The tendency of each structure toward certain product distributions was related to the reaction
mechanism by establishing a structure-reactivity correlation, when the
experiment results were combined with theoretical calculations. It is proposed
that different shape of the cavities stabilize different precursor intermediates
present in the paring or side-chain pathways and this indicates the reaction
preference between each pathway and therefore the product distributions. A
linear correlation was obtained between the shape of cavities and the C3
=
/C2
=
molar ratios being possible. In this way, ITQ-3 (ITE structure) was predicted
that should also give higher selectivity toward paring pathway, which has been
demonstrated experimentally[ES] La presente tesis se centra en la racionalización de la síntesis de zeolitas para su
aplicación como catalizadores mediante la comprensión de la naturaleza de los
sitios activos y sus microambientes, junto con su influencia en los mecanismos
de las reacciones catalizadas.
En la primera parte de la tesis, se han realizado esfuerzos para intentar lograr la
ubicación regioselectiva de los sitios activos en el catalizador zeolítico y, más
específicamente, en la ubicación controlada de sitios ácidos en la red cristalina
de la zeolita. El desarrollo de una estrategia de síntesis adecuada junto con un
indicador que pueda describir la distribución de aluminio en la red de la zeolita
es importante para evaluar si se ha logrado el objetivo final. En esta parte, para
evaluar la distribución de aluminio en la red de la zeolita MFI, se ha propuesto
un indicador basado en los mecanismos monomoleculares y bimoleculares
asociados a la reacción de craqueo catalítico de n-hexeno. En primer lugar, se
sintetizaron varias muestras de ZSM-5, que según la literatura tienen diferentes
distribuciones de aluminio. Estas muestras se caracterizaron por ser análogas en
propiedades fisicoquímicas y, posteriormente, se analizaron en la reacción de
craqueo de n-hexeno para justificar la utilidad del indicador propuesto en este
trabajo. A partir de RMN MAS de 27Al se demostró que las ubicaciones de
aluminio eran diferentes, lo que también se reflejó en el indicador propuesto en
esta tesis, lo que justifica su aplicabilidad para evaluar distribuciones de aluminio.
Posteriormente, este indicador se ha empleado para verificar la nueva
metodología de síntesis de zeolitas que podría conducir a una distribución de
aluminio diferente en sus estructuras cristalinas. En este sentido, se propone la
síntesis de la zeolita ZSM-5 asistida por boro, considerando que el boro y el
aluminio podrían tener un posicionamiento competitivo en la estructura MFI.
Mediante cálculos de DFT, se ha estudiado si la celda unidad de MFI muestra
diferente estabilidad cuando se introduce aluminio y/o boro en diferentes
posiciones cristalográficas T. Se ha encontrado que la ubicación del boro está
menos favorecida cuando se introduce en los canales de 10 miembros de la estructura MFI, mientras que el aluminio no muestra preferencia por el
posicionamiento entre todos los sitios T. Se sintetizaron muestras de ZSM-5 con
diferentes Si/Al y Si/B y se caracterizaron sus propiedades fisicoquímicas, así
como la proporción relativa de estados emparejados y aislados de aluminio. La
caracterización incluye el craqueo de n-hexeno, para el cual las muestras
mostraron una preferencia diferente hacia las reacciones monomoleculares y
bimoleculares. Finalmente, una vez demostrada la distinta distribución de
aluminio en los materiales sintetizados, estos catalizadores se estudiaron en la
reaccióde metanol a propeno (MTP) para mostrar la influencia de la distribución
de aluminio en una reacción relevante a nivel industrial, donde el confinamiento
espacial tiene un impacto importante. De hecho, las muestras con aluminio
posicionadas preferentemente en un canal de 10 miembros favorecen reacciones
de craqueo monomolecular frente a reacciones secundarias bimoleculares, como
por ejemplo reacciones de oligomerización y de transferencia de hidrógeno,
dando un mayor rendimiento a propeno y una menor cantidad de alcanos y
compuestos aromáticos.
La segunda parte de la tesis se centra en racionalizar la síntesis de zeolitas con
cavidades para catalizar una reacción seleccionada "a priori". Más
específicamente, la síntesis de zeolita se llevó a cabo utilizando agentes directores
de estructura orgánicos (ADEO) que mimetizan el estado de transición (ET) o
el intermedio relevante en la reacción objetivo. La producción de etilbenceno
por transalquilación entre dietilbenceno y benceno se ha seleccionado como una
reacción objetivo a catalizar. Se estableció el ET determinante de la reacción y
se sintetizó un ADEO tipo diarildimetilfosfonio que mimetiza el estado de
transición del mecanismo de la reacción de transalquilación entre benceno y
dietilbenceno. Dicho ADEO permitió la cristalización de la zeolita de poro
grande ITQ-27, cuyo comportamiento catalítico se estudió en la reacción de
transalquilación entre benceno y dietilbenceno. La actividad catalítica de la
zeolita ITQ-27 se mostró claramente superior al de otras zeolitas empleadas
comercialmente, como USY, mordenita o Beta, todas ellas con propiedades
fisicoquímicas similares a la ITQ-27. Finalmente, la reacción de metanol a olefinas (MTO) se eligió como otro sistema
catalítico objetivo, donde los mecanismos de reacción son mucho más
complicados que en el caso de la reacción de transalquilación entre benceno y
dietilbenceno, pero, sin embargo, están bien establecidos en la literatura. Se
sintetizaron varios ADEOs que mimetizan los intermedios y los estados de
transición de la ruta “paring”, que produce más propeno y butenos, y que son
posiblemente los productos más demandados. Dichos ADEOs mímicos
permitieron la formación de varias zeolitas de poro pequeño basadas en
cavidades, como las zeolitas CHA, RTH y AEI. Todas las zeolitas obtenidas se
probaron en la reacción MTO para evaluar su actividad catalítica, obteniéndose
una alta selectividad hacia distintas olefinas ligeras, cuya selectividad depende de
la forma y tamaño de la cavidad de cada zeolita. La tendencia de cada estructura
hacia ciertas distribuciones de productos se ha relacionado con el mecanismo de
reacción, pudiendo establecer una correlación estructura-reactividad al combinar
los resultados experimentales con cálculos teóricos.[CA] La present tesi es centra en la racionalització de la síntesi de zeolites per a la seva
aplicació com a catalitzadors mitjançant la comprensió de la naturalesa dels
centres actius i els seus microambientes, juntament amb la seva influència en els
mecanismes de les reaccions catalitzades.
A la primera part de la tesi, s'han realitzat esforços per intentar aconseguir la
ubicació regioselectiva dels centres actius en el catalitzador zeolític i, més
específicament, en la ubicació controlada de centres àcids en la xarxa cristal·lina
de la zeolita. El desenvolupament d'una estratègia de síntesi adequada juntament
amb un indicador que descriga la distribució d'alumini a la xarxa de la zeolita és
important per avaluar si s'ha aconseguit l'objectiu final. En aquesta part, per
avaluar la distribució d'alumini a la xarxa de la zeolita MFI, s'ha proposat un
indicador basat en els mecanismes monomoleculares i bimoleculars associats a
la reacció de craqueig catalític de n-hexé. En primer lloc, es van sintetitzar
diverses mostres de ZSM-5, que segons la literatura tenen diferents distribucions
d'alumini. Aquestes mostres es van caracteritzar per ser anàlogues en propietats
fisicoquímiques i, posteriorment, es van analitzar en la reacció de craqueig de nhexéper justificar la utilitat de l'indicador proposat en aquest treball. A partir
dels espectres de RMN MAS de 27Al es va demostrar que les ubicacions d'alumini
eren diferents, el que també es va reflectir en l'indicador proposat en aquesta tesi,
justificant la seva aplicabilitat per avaluar distintes distribucions d'alumini.
Posteriorment, aquest indicador s'ha emprat per verificar la nova metodologia
de síntesi de zeolites que podria conduir a una distribució d'alumini diferent al
llarg de les seves estructures cristal·lines. En aquest sentit, s’ha proposat la síntesi
de la zeolita ZSM-5 assistida per bor, considerant que el bor i l'alumini podrien
tenir un posicionament competitiu en l'estructura MFI. Mitjançant càlculs de
DFT, s'ha estudiat si la cel·la unitat de MFI mostra diferent estabilitat quan
s’introdueix alumini i/o bor en diferents posicions cristal·logràfiques T. S'ha
trobat que la ubicació dels àtoms de bor està menys afavorida als canals de 10
membres de la estructura MFI, mentre que l'alumini no mostra preferència pel
posicionament entre tots els llocs T. Es van sintetitzar mostres de ZSM-5 amb diferents relacions de Si/Al i Si/B i es van caracteritzar les seves propietats
fisicoquímiques, així com la proporció relativa d'estats aparellats i aïllats
d'alumini. La caracterització inclou la reacció de craqueig de n-hexé, on les
mostres van mostrar una preferència diferent cap a les reaccions
monomoleculares i bimoleculars. Finalment, un cop demostrada la diferent
distribució d'alumini en els materials sintetitzats, aquests catalitzadors es van
estudiar a la reacció de metanol a propè (MTP) per mostrar la influència de la
distribució d'alumini en una reacció rellevant a nivell industrial, on el
confinament espacial té un impacte important. De fet, les mostres amb alumini
posicionades preferentment en un canal de 10 membres afavoreixen reaccions
de craqueig monomolecular enfront de reaccions secundàries bimoleculars, com
ara reaccions d'oligomerització i de transferència d'hidrogen, donant un major
rendiment a propè i una menor quantitat d'alcans i compostos aromàtics.
La segona part de la tesi es centra en racionalitzar la síntesi de zeolites amb
cavitats per catalitzar una reacció seleccionada "a priori". Més específicament, la
síntesi de zeolita es va dur a terme utilitzant agents directors d'estructura orgànics
(ADEO) que mimetitzen l'estat de transició (ET) o l'intermedi rellevant en la
reacció objectiu. La producció de etilbenzèper transalquilació entre dietilbenzè
i benzè s'ha seleccionat com una reacció objectiu a catalitzar. Es va establir l'ET
determinant de la reacció i es va sintetitzar un ADEO tipus diarildimetilfosfoni
que mimetitza eixe estat de transició. Eixe ADEO va permetre la cristal·lització
de la zeolita de porus gran ITQ-27, i el seu comportament catalític es va estudiar
en la reacció de transalquilación entre benzè i dietilbenzè. L'activitat catalítica de
la zeolita ITQ-27 es va mostrar clarament superior a la d'altres zeolites emprades
comercialment, com la USY, mordenita o Beta, totes elles amb propietats
fisicoquímiques similars a la ITQ-27.
Finalment, la reacció de metanol a olefines (MTO) es va triar com un altre
sistema catalític objectiu, on els mecanismes de reacció són molt més complicats
que en el cas de la reacció de transalquilació entre benzè i dietilbenzè, però que,
al mateix temps, estan ben establerts en la literatura. Es van sintetitzar diversos
ADEOs que mimetitzen alguns dels intermedis i dels estats de transició de la
ruta "paring", que produeix més propè i butens, i que són possiblement els productes més demandats. Aquests ADEOs mímics van permetre la formació
de diverses zeolites de porus petit basades en cavitats, com les zeolites CHA,
RTH i AEI. Totes les zeolites obtingudes es van provar en la reacció MTO per
avaluar la seva activitat catalítica, obtenint una alta selectivitat cap a diferents
olefines lleugeres, on la selectivitat cap a cada olefina lleugera depèn de la forma
i mida de la cavitat de cada zeolita. La tendència de cada estructura cap a certes
distribucions de productes s'ha relacionat amb el mecanisme de reacció, i s´ha
pogut establir una correlació estructura-reactivitat al combinar els resultats
experimentals amb càlculs teòrics.Li, C. (2020). Rationalize the synthesis of zeolite catalysts by understanding reaction mechanism [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/147115TESI
셀룰로오스 나노섬유 매트릭스 지지 3차원 프린팅
학위논문(박사)--서울대학교 대학원 :농업생명과학대학 바이오시스템·소재학부(바이오소재공학전공),2020. 2. 현진호.Cellulose nanofibers (CNFs) are attracting material for a three-dimensional (3D) printing matrix due to excellent rheological characteristics. In 3D printing with CNFs, a nozzle moves through the viscoelastic CNF matrix and makes patterns with ink materials. Rheological properties of CNFs are related to various factors including fiber dimension and concentration of CNFs in the aqueous dispersion, and influence on the printing fidelity. The different morphology of CNFs was prepared by varying the degree of carboxymethylation with CNFs. The printing fidelity was evaluated by observing the shape of ink features that were printed directly inside the CNF matrix. The relationship between the rheological properties of the CNF matrix and the printing fidelity was investigated on the printing speed, strain fields, and yielded regions. The cell-containing bio-ink and hydrophobic silicon-based inks were printed in the CNF matrix in a complex structure with high printing fidelity. Amazingly, the structure printed freely in the CNF hydrogels was able to retain its highly resolved 3D features in an ultrathin two-dimensional (2D) paper using a simple drying process. The dimensional change in the CNF hydrogels from 3D to 2D resulted from simple dehydration of the CNFs and provided transparent, stackable paper-based 3D channel devices. The CNF devices exhibited selective diffusion of molecules from the channel wall, indicating the applicability for the sensor and the cell culture platforms.본 논문에서는 셀룰로오스 나노섬유 하이드로겔을 3D 프린팅 매트릭스로 활용하기 위한 전략과 프린팅 충실도를 평가하기 위한 기준을 제시하였고, 건조 시 얇고 투명한 필름을 제조할 수 있다는 특성을 바탕으로 마이크로유체칩을 제조하였다.
셀룰로오스 나노섬유는 3차원 인쇄에 적합한 유변학적 특성으로 인해 최근 3D 프린팅 분야에서 주목을 받아왔으며, 3D 프린팅 잉크로의 활용 가능성이 높은 재료이다. 그러나 하이드로겔 잉크는 변형에 취약하여 기존의 프린팅 기술로는 3차원 구조물을 제조하는데 한계가 있어, 구조물을 지지해줄 수 있는 매트릭스 재료를 활용한 매트릭스 지원 3D 프린팅 기술이 제안되었다. 현재까지 셀룰로오스 나노섬유를 3D 프린팅 매트릭스로 활용하고자 하는 연구는 보고된 바가 없으며 본 연구에서는 셀룰로오스 나노섬유가 3D 프린팅 매트릭스로 활용되기 위한 최적의 조건을 탐색하였다.
셀룰로오스 나노섬유의 유변학적 특성은 섬유의 크기 및 농도에 의해 결정된다. 본 연구에서는 섬유의 크기를 카르복시메틸화를 통해 조절하였으며, 다양한 농도 조건에서의 프린팅 충실도를 평가하기 위한 기준을 제시하였다. 프린팅 충실도는 셀룰로오스 나노섬유 매트릭스와 혼화성의 차이를 보이는 친수성, 소수성 모델 잉크를 프린팅 하고 잉크의 형상을 관찰하여 평가하는 방식으로 진행하였다. 각이진 선을 프린팅 하고 각도의 날카로운 정도와 잉크의 단면 비율, 그리고 잉크 표면 거칠기를 분석하여 매트릭스의 유변학적 특성과 프린팅 충실도 간의 관계를 분석하였다. 이를 활용하여 셀룰로오스 나노섬유 매트릭스 내부에 바이오 잉크를 프린팅 할 수 있었으며 소수성 실리콘 기반 잉크로 복잡한 3차원 구조체를 제조할 수 있었다.
셀룰로오스 나노섬유는 프린팅 매트릭스로 활용될 수 있을 뿐만 아니라 간단한 건조과정을 통해 얇고 투명한 디바이스를 제조하기 최적화 되어있는 재료이다. 이러한 장점을 활용하여 셀룰로오스 나노섬유 기반의 마이크로유체칩을 제조할 수 있었다. 셀룰로오스 나노섬유의 투명도와 물질확산특성은 화학 센서뿐만 아니라 세포를 배양하고 세포의 거동을 분석할 수 있는 세포 배양 플랫폼으로도 활용될 수 있었다.Ⅰ. Introduction 1
Ⅱ. Literature Survey 4
2.1. Various 3D printing technologies 4
2.2. Matrix-assisted 3D printing (MAP) 8
2.2.1. Rheological requirements for MAP 10
2.2.2. Various matrix systems for MAP 11
2.3. Cellulose 16
2.3.1. Cellulose nanofiber (CNF) 17
2.3.2. Extraction methods of CNF 18
2.3.3. Rheological properties of CNF 21
2.4. CNF as a 3D printing material 23
2.4.1. CNF as a rheology modifier 23
2.4.2. CNF as a reinforcement 24
2.5. CNF based devices 27
2.5.1. Transparent and thin device through dehydration 27
2.5.2. Electronic devices 28
2.5.3. Biological and chemical sensing devices 29
2.5.4. Cell culture devices 30
Ⅲ. Materials and Methods 32
3.1. Preparation and characterization of the CNF matrix 32
3.2. Preparation of various types of ink 33
3.2.1. Cross-linked polyacrylic acid-based model ink 33
3.2.2. CNF based bio-ink 34
3.2.3. Petroleum-jelly based removable ink 34
3.2.4. Silicone ink-based curable ink 34
3.3. Rheological properties of CNF matrices and inks 35
3.4. Matrix-assisted 3D printing of a single line 35
3.4.1. Matrix-assisted 3D printing of straight line 35
3.4.2. Matrix-assisted 3D printing of angled line 36
3.5. Matrix-assisted 3D printing of multi-lines 36
3.5.1. Matrix-assisted 3D printing of multi-lines 36
3.5.2. Particle Image Velocimetry (PIV) test 36
3.6. Living cell embedded bio-ink printing 37
3.7. Silicone actuator printing 37
3.8. Fabrication of CNF based open-channel microfluidic devices 38
3.8.1. Fabrication process of CNF microfluidic devices 38
3.8.2. CNF based pH sensor 39
3.8.3. CNF based heavy metal sensor 39
3.9. Fabrication of CNF based open cell culture platform 40
3.9.1. Hydrophobic treatment of CNF 40
3.9.2. Mass transfer test at the CNF layers 41
3.9.3. Cell culture on CNF microfluidic devices 41
3.10. Imaging 42
Ⅳ. Results and Discussion 43
4.1. Properties of carboxymethylated CNF matrix 43
4.2. Rheological properties of CNF matrix 52
4.2.1. Shear-thinning property of CNF matrix 52
4.2.2. Yielding property of CNF matrix 55
4.2.3. Creep and recovery properties of CNF matrix 58
4.3. Evaluation of printing fidelity in a single printing line feature 60
4.3.1. Evaluation of printing fidelity by sharpness of angled-line 60
4.3.2. Evaluation of printing fidelity by cross-sectional ratio 66
4.3.3. Evaluation of printing fidelity by straightness of line surface 69
4.3.4. Evaluation of printing fidelity with hydrophobic ink 74
4.4. Evaluation of printing fidelity in multi printing lines feature 82
4.4.1. Particle image velocimetry (PIV) test 82
4.4.2. Velocity magnitude around nozzle 86
4.4.3. Matrix composition and printing path effects on fidelity 88
4.5. Printing of various ink materials 90
4.5.1. Rheological properties of various ink materials 90
4.5.2. Living cell embedded 3D bio-printing 92
4.5.3. Feasibility test of printed silicone actuator 92
4.6. Fabrication of CNF based open-channel microfluidic devices 95
4.6.1. Feasibility test of microfluidic channel devices 97
4.6.2. Control of channel diameters 99
4.6.3. Dimension control of the microfluidic device 101
4.6.4. Feasibility of pH sensor 103
4.6.5. Colorimetric analysis of heavy metal ions 105
4.7. Fabrication of CNF based open cell culture platform 107
4.7.1. Evaluation of hydrophobicity of MTMS treated CNF 111
4.7.2. Diffusion of FITC-Dex to CNF channel layers 114
4.7.3. Cell viability of the CNF-based platform 117
4.7.4. Effect of cisplatin at the CNF-based platform 118
Ⅴ. Conclusion 121
Ⅵ. References 123Docto
Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation
The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (μ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.Fil: Santana Romo, Fabián. Pontificia Universidad Católica de Chile; ChileFil: Lagos, Carlos F.. Universidad San Sebastián; ChileFil: Duarte, Yorley. Universidad Andrés Bello; ChileFil: Castillo, Francisco. Pontificia Universidad Católica de Chile; ChileFil: Moglie, Yanina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Maestro, Miguel A.. University of A Coruña; EspañaFil: Charbe, Nitin. Pontificia Universidad Católica de Chile; ChileFil: Zacconi, Flavia Cristina Milagro. Pontificia Universidad Católica de Chile; Chil
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