Dissertations / Theses on the topic 'Host-Guest inclusion complex'

In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next. Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state. In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments. The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.

Thesis (MSc)--Stellenbosch University, 2011.
ENGLISH ABSTRACT: 2,7-dimethylocta-3,5-diyne-2,7-diol forms inclusion complexes with various guests molecules, where the guest molecules are polar-ordered. A Cambridge Structural Database (CSD) search revealed ten inclusion complexes where the guest molecules were polar-ordered. Using Density Functional Theory (DFT) computational methods (in the absence of the host), we evaluated the intra-channel and lateral guest-guest interactions between the guest molecules. Two polar-ordered inclusion complexes ((1,4,7-cyclohexane-1,2,4,5,7,8-hexaoxonane)·CHCl3 and (2,4,6-(endolongifolyl)-1,3,5-trioxane)·CDCl3) were singled out in the CSD search for further studies along with 2,7-dimethylocta-3,5-diyne-2,7-diol. Synthesis of any 1,2,4,5,7,8-hexaoxonane and 1,3,5-trioxane derivatives was attempted to establish whether the polar-ordering ability extends into the family of compounds. We managed to produce three new polar-ordered inclusion complexes with 2,7-dimethylocta-3,5-diyne-2,7-diol (ClC(CH3)3, BrC(CH3)3 and IC(CH3)3), thus extending the series to six guest polar-ordered systems. We were only able to synthesise 1,4,7-cyclohexane-1,2,4,5,7,8-hexaoxonane and produce the CHCl3 inclusion complex and one new polar-ordered inclusion complex (CHBr3). Three 1,3,5-trioxanes was synthesised (the cyclohexyl, cyclohex-3-en-1-yl and cyclopentyl derivatives), which did not include any solvents. However, these 1,3,5-trioxanes also form polar-ordered crystals. These compounds and inclusion complexes were analysed by means of single crystal X-ray diffraction to determine their crystal structures. All the crystal structures could be solved and refined to adequate accuracy (except for 2,4,6-tri(cyclopentyl)-1,3,5-trioxane) with no disorder of the guest molecules (where applicable) and their polar-ordering property investigated. Due to their vast molecular differences, these compounds were studied separately by means of visual crystal structure analysis and computational modelling techniques (Density functional theory, molecular mechanics, molecular dynamics and molecular quench dynamics).
AFRIKAANSE OPSOMMING: 2,7-dimetielokta-3,5-diyn-2,7-diol vorm insluitingskomplekse met verskeie molekules as gaste, waar die gas-molekules polêr georden is. 'n Cambridge Struktuur Databasis (CSD) soektog lewer tien insluitings komplekse waarvan die gas-molekules polêr georden is. Deur gebruik te maak van Digtheidsfunksionele teorie (DFT) berekeninge (in die afwesigheid van die gasheer) het ons die inter-kanaal en wedersydse gas-gas interaksies tussen die gas molekules geëvalueer. Twee polêr geordende insluitingskomplekse ((1,4,7-sikloheksaan-1,2,4,5,7,8-heksaoksonaan)·CHCl3 en (2,4,6-(endolongifolyl)-1,3,5-trioksaan)·CDCl3) is uitgesonder uit die CSD soektog vir verdere studies saam met 2,7-dimetielokta-3,5-diyn-2,7-diol. Aanslag was gemaak om enige 1,2,4,5,7,8-heksaoksonaan en 1,3,5-trioksaan derivate te sintetiseer en vas te stel of die polêre ordensvermoë oor die familie van verbindings strek. Ons het daarin geslaag om drie nuwe polêr geordende insluitingskomplekse op te lewer met 2,7-dimetielokta-3,5-diyn-2,7-diol (Cl(CH3)3, BrC(CH3)3 en I(CH3)3), en sodoende die reeks uitgebrei na ses gaste wat polêr geordende insluitingskomplekse vorm. Net 1,4,7-sikloheksaan-1,2,4,5,7,8-heksaoksonaan kon gesintetiseer word en dit lewer twee polêr geordende insluitingskomplekse (CHCl3 en CHBr3 (nuut)). Drie 1,3,5-trioksane is gesintetiseer (die sikloheksiel, sikloheks-3-een-1-iel en siklopentiel derivate) en het nie enige oplosmiddels (gaste) ingesluit nie. Nietemin vorm hiedie 1,3,5-trioksane ook polêr geordende kristalle. Hierdie verbindings en insluitingskomplekse is geanaliseer deur middel van enkelkristal X-straal diffraksie om hul kristalstrukture te bepaal. Alle kristalstrukture was opgelos en verwerk tot voldoende akkuraatheid (behalwe vir 2,4,6-tri(siklopentiel)-1,3,5-trioxane) met geen wanorde in die gas molekuul posisies nie (waar van toepassing) en hul polêre ordensvermoë is ondersoek. As gevolg van groot verskille in hul molekulêre strukture, is hierdie verbindings afsonderlik bestudeer deur middel van molekulêre modellerings metodes (Digtheidsfunksionele teorie, molekulêre meganika, molekulêre dinamika en molekulêre stakings dinamika).

Cyclophanes are macromolecules that are known to effectively bind with molecules to form host-guest complexes. Several cyclophane molecules, referred to as corrals (1-6) by their founders, have been synthesized. The characterization of these compounds and their complexes has been investigated using combined spectroscopic and theoretical methods. Hostguest interactions of cyclophane-anthracene (C-A), cyclophane-9-fluorenone (C-F) and cyclophane-pyrene (C-P) complex systems in dichloromethane are presented in this thesis. The stability constants, log Ka, for the C-A, C-F and C-P complexes are determined using absorption and fluorescence spectroscopy. Heats of formation of corral 2 complexes were determined by measuring the complex association constants at 25, 29 and 32 °C. Results reveal that binding of the non-polar guests by the cyclophane molecules are thermodynamically favored over binding with polar guest. Computational studies indicate difference in energy due to solvent effect of the complexes in the condensed phase. Excited state lifetimes of these systems are also determined, and they support fluorescence as a path of relaxing back to the ground state.

NMR is a powerful analytical spectroscopic tool used to perform detailed studies of structure and dynamics of molecules in solution. However, despite NMR's excellent spectral sensitivity, most NMR methods suffer from low detection sensitivity. This low detection sensitivity results largely from extremely small (Boltzmann) nuclear spin polarization at thermal equilibrium--in even the strongest of magnets. This dissertation focuses on selected research areas that maybe used to combat the limitations presented by NMR and measure weak spectral responses with atomic-scale precision. In particular, these methods involve the use of laser-polarized xenon, liquid crystals, and polarization transfer (cross-polarization) techniques to enhance NMR sensitivity and/or measure weak interactions. The potential use of these tools to study host-guest interactions is of particular interest. In certain systems the sensitivity problem of conventional NMR/MRI can be overcome by applying optical pumping (OP) methods to enhance nuclear spin polarization. For instance, OP of noble gases (such as xenon) is employed to dramatically increase their nuclear spin polarization by transferring angular momentum of laser light to electronic and then nuclear spins. Next, cryptophane complexes are ideal choices for fundamental studies of prototypical host-guest interactions. Of general interest when studying host-guest interactions is how (1) physical confinement at the nanoscale and (2) interactions between guest and host may affect the properties, dynamics, interactions, and/or reactivity of a trapped molecule and the host/guest complex as a whole. As a more specific example, we are interested in probing host-guest dynamic coupling, which refers to the relative motion of the guest within the host, determined by the relative sizes and geometries--as well as the interactions involved. With the development of new NMR methods and techniques, we hope to gain insight into mechanisms that underlie complex formation by probing the structures, dynamics and energetic contributions involved in ligand binding, where molecular contributions such as: orientational and motional freedom of the guest; and structure, dynamics, and ordering of the host can influence the behavior of inclusion complexes.

Host–guest complexes are widely investigated because of their importance in many industrial applications. The investigation of their physico–chemical properties helps understanding the inclusion phenomenon. The hosts investigated in this work are cryptophane molecules possessing a hydrophobic cavity. They can encapsulate small organic guests such as halo–methanes (CH2Cl2, CHCl3). The encapsulation process was investigated from both the guest and the host point of view. With the help of Nuclear Magnetic Resonance (NMR), the kinetics of complex formation was determined. The information was further used to obtain the activation energies of the processes. Having done this on five different cryptophanes, it is possible to relate the energies to structural differences between the hosts. Via the dipolar interaction between the guest’s and host’s protons, one can get information on the orientation of the guest inside the cavity. Moreover, the dynamics of the guest can be further investigated by its relaxation properties. This revealed restricted motion of the guest inside the host cavity. Not only the nature of the guest plays an important role. The host is also changing its properties upon encapsulation. All the cryptophanes investigated here can exchange rapidly between many conformers. These conformers have different–sized cavities. Quantum chemical optimization of the structure of the conformers makes volume estimation possible. Not only the cavity volumes, but also the quantum-chemically obtained energies and the calculated chemical shifts of the carbon–13 atoms can be helpful to follow the changes of the host upon complex formation. The host cannot be considered as a rigid entity. Analysis of variable temperature proton and carbon-13 spectra shows that the encapsulation can be considered as a mixture of conformational selection and induced fit. The structures of the formed complexes are further investigated by means of two-dimensional nuclear Overhauser spectroscopy (NOESY). The complex formation, its kinetics and thermodynamics are found to be a complicated function of structure elements of the host, the cavity size and the guest size and properties.

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Accepted. Paper 5: Manuscript.

 

Aquesta Tesi s'ocupa del disseny i síntesi de receptors còncaus que posseeixen cavitats hidrofíliques: receptors covalents, caixes metàl·liques i càpsules no covalents. Per a la seva construcció, triem la bastida de calix[4]pirrol aril-estès (C[4]P-AE), que proporciona una cavitat aromàtica profunda tancada en un extrem per un lloc d'unió polar i oberta a l'extrem oposat. També investiguem les propietats de reconeixement dels receptors sintetitzats en dissolvents orgànics així com en aigua. Específicament, descrivim un mètode sintètic per l'allargament de la cavitat de C[4]P-AEs que condueix a derivats súper aril-estesos (C[4]P-SAE). Primer, vam preparar un C[4]P-SAE tetra-èster i realitzem estudis d'enllaç amb una sèrie de N-òxids en dissolució de cloroform. Els complexos del C[4]P-SAE tenien una estequiometria 1:1 i eren termodinàmicament i cinèticament altament estables. Els resultats destaquen les propietats d'unió superiors del receptor C[4]P-SAE davant l'inicial aril-estès. A continuació, sintetitzem C[4]P-SAEs amb vuit grups ionitzables (octa-àcid) o carregats (octa-piridini). Els últims C[4]P-SAEs eren solubles en aigua bàsica o neutra. Nosaltres vam determinar l'estabilitat termodinàmica dels seus complexos d'inclusió amb una sèrie de N-òxids de piridina, que tenien diferents residus no polars en la seva posició per. En base a aquests resultats, quantifiquem la magnitud de l'efecte hidrofòbic que opera a aquests complexos de C[4]P-SAE. També reportem l'auto-assamblatge de caixes metàl·liques i càpsules, que presenten cavitats tancades. Referent a això, vam mostrar que un lligant C[4]P-SAE tetra-piridina s'auto-assembla en una caixa mono-metàl·lica de Pd(II)/Pt(II). Estudiem l'encapsulació de substrats polars de mida considerables en la cavitat de la caixa. Els resultats obtinguts en la caracterització cinètica dels complexos de la caixa ens van permetre proposar mecanismes d'inclusió/intercanvi dels substrats. Finalment, descrivim els estudis de dimerització d'una tetra-urea basada en un SAE-C[4]P per donar càpsules no covalents estabilitzades per enllaços d'hidrogen.
Esta Tesis se ocupa del diseño y síntesis de receptores cóncavos que poseen cavidades hidrofílicas: receptores covalentes, cajas metálicas y cápsulas no covalentes. Para su construcción, elegimos el andamio de calix[4]pirrol aril-extendido (C[4]P-AE), que proporciona una cavidad aromática profunda cerrada en un extremo por un sitio de unión polar y abierta en el extremo opuesto. Nosotros investigamos las propiedades de reconocimiento molecular de los receptores sintetizados tanto en disolventes orgánicos como en agua. Específicamente, describimos un método sintético para el alargamiento de la cavidad de C[4]P-AEs que conduce a derivados súper aril-extendidos (C[4]P-SAE). Primero, preparamos un C[4]P-SAE tetra-éster y realizamos estudios de enlace con una serie de N-óxidos en disolución de cloroformo. Los complejos del C[4]P-SAE tenían una estequiometría 1:1 y eran termodinámicamente y cinéticamente altamente estables. Los resultados destacan las propiedades de unión superiores del receptor C[4]P-SAE frente al inicial aril-extendido. A continuación, sintetizamos C[4]P-SAEs con ocho grupos ionizables (octa-ácido) o cargados (octa-piridinio). Los últimos C[4]P-SAEs eran solubles en agua básica o neutra. Nosotros determinamos la estabilidad termodinámica de sus complejos de inclusión con una serie de N-óxidos de piridina, que tenían diferentes residuos no polares en su posición para. En base a estos resultados, cuantificamos la magnitud del efecto hidrofóbico que opera en estos complejos de C[4]P-SAE. También reportamos el auto-ensamblaje de cajas metálicas y cápsulas no covalentes, que presentan cavidades cerradas. A este respecto, mostramos que un ligando C[4]P-SAE tetra-piridina se auto-ensambla en una caja mono-metálica de Pd(II)/Pt(II). Estudiamos la encapsulación de substratos polares neutros en la cavidad de la caja. Los resultados obtenidos en la caracterización cinética de los complejos de la caja nos permitieron proponer mecanismos para los procesos de inclusión/intercambio de los sustratos. Finalmente, describimos los estudios de dimerización de un SAE-C[4]P tetra-urea en cápsulas diméricas estabilizadas a través de interacciones de enlaces de hidrógeno.
This Thesis deals with the design and synthesis of concave receptors possessing hydrophilic cavities: covalent receptors, metallo-cages and non-covalent capsules. For their construction, we chose the aryl-extended calix[4]pyrrole scaffold (AE-C[4]P), which delivers a deep aromatic cavity closed at one end by a polar binding site and opened at the opposite end. We investigated the binding properties of the synthesized receptors in both organic solvents and water. Specifically, we describe a synthetic approach for the elongation of the cavity of AE-C[4]Ps leading to super aryl-extended derivatives (SAE-C[4]P). First, we prepared a tetra-ester SAE-C[4]P and conducted binding studies with a series of N-oxides in chloroform solution. The SAE-C[4]P complexes had 1:1 stoichiometry and were thermodynamically and kinetically highly stable. The results highlight the superior binding properties of the SAE-C[4]P receptor versus the parent aryl-extended. Next, we synthesized SAE-C[4]Ps bearing eight ionizable (octa-acid) or charged (octa-pyridinium) groups. The later SAE-C[4]Ps were soluble in basic or neutral water. We determined the thermodynamic stability of their inclusion complexes with a series of pyridyl N-oxides, having different non-polar residues at their para-position. Based on these results, we quantified the magnitude of the hydrophobic effect operating in these SAE-C[4]P complexes. We also report the self-assembly of metallo-cages and non-covalent capsules, featuring enclosed cavities. In this regard, we show that a tetra-pyridyl SAE-C[4]P ligand self-assembles into a mono-metallic Pd(II)/Pt(II)-cage. We studied the encapsulation of neutral polar guests in the cage’s cavity. The results obtained in the kinetic characterization of the cage complexes allowed us to propose viable mechanisms for the guest inclusion/exchange processes. Finally, we describe the dimerization studies of a tetra-urea SAE-C[4]P into dimeric capsules stabilized through hydrogen-bonding interactions.

Synthesis of cyclodextrin derivatives for practical applications Abstract The first part of this PhD thesis is focused on the synthesis of a series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives. The emphasis was placed on the possible applicability of the synthetic process to multigram or even industrial scale. Monotosylation of the native cyclodextrins (-, -, -) on the primary side of the macrocycle afforded the starting materials. Derivatives with one cationic group were prepared by the reaction with aqueous trimethylamine. The reaction of the mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'-trimethylpropane-1,3-diamine and subsequent methylation led to derivatives with the substituent bearing two cationic groups (PEMEDA- and PEMPDA-β-CD). Analogs bearing a moiety with three tetraalkylammonium sites were synthesized by reaction of mono-Ts-CD with bis(3-aminopropyl)amine with subsequent methylation. 1,3-Dipolar cycloaddition of mono-6- azido--CD with diaminoacetylenes followed by methylation led to analogs with a avariable distance of the charged substituent from the CD core. Majority of the presented reactions are straightforward, relatively high-yielding and the workup does not require chromatographic steps. The second part of the work is dealing with the...

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
Parenteral formulations are indispensable in clinical practice, and often consist of the only option to administer drugs not able to be administrated through other routes, such as proteins and certain anticancer drugs, which are indispensable to treat some of the most prevailing chronic diseases worldwide, as diabetes and cancer. Additionally, parenteral formulations play a relevant role in emergency care since they are the only ones which provide an immediate action of the drug upon administration. However, the development of parenteral formulations is a complex task owing to the specific quality and safety requirements set for these preparations, and to the intrinsic properties of the drugs.Amongst all the strategies that can be useful in the development of parenteral formulations, the formation of water-soluble host-guest inclusion complexes with cyclodextrins (CDs) has proven to be the most advantageous. CDs are multifunctional pharmaceutical excipients able to form water-soluble host-guest inclusion complexes with a wide variety of molecules, particularly drugs, and thus improve their water solubility, chemical stability, and bioavailability, in order to make them suitable for parenteral administration. Besides, CDs are able to be employed as building blocks of more complex injectable drug delivery systems with enhanced characteristics, such as nanoparticles and supramolecular hydrogels that have been found particularly beneficial for the delivery of anticancer drugs. However, only few CDs are considered safe when parenterally administered, and some of these types of CDs are already approved to be used in parenteral dosage forms. Therefore, the application of CDs in the development of parenteral formulations has been a more common practice in the last few years, due to their significative worldwide acceptance by the health authorities, stimulating the development of safer and efficient injectable drug delivery systems.
As formulações parentéricas são indispensáveis na prática clínica e, por vezes, consistem na única opção disponível para a administração de determinados fármacos, quando não existe possibilidade destes serem administrados por outras vias, como é o caso das proteínas e de certos fármacos anticancerígenos, que são fundamentais para o tratamento de algumas das doenças crónicas mais prevalentes a nível global, como a diabetes e o cancro. Além disso, as formulações parentéricas apresentam um papel extremamente importante em situações de emergência, uma vez que são as únicas que permitem uma ação imediata do fármaco após a administração. Contudo, o desenvolvimento de formulações parentéricas é uma tarefa complexa, devido aos requisitos de qualidade e segurança a que estas formulações estão sujeitas, e às propriedades intrínsecas dos fármacos, nomeadamente a baixa estabilidade e solubilidade aquosa. Considerando as várias estratégias existentes para o desenvolvimento de formulações parentéricas, a formação de complexos de inclusão hidrossolúveis com ciclodextrinas (CDs) tem-se revelado bastante benéfica. As CDs são excipientes farmacêuticos versáteis, capazes de formar complexos de inclusão com uma vasta gama de moléculas, em particular fármacos, de modo a melhorar a sua solubilidade aquosa, estabilidade química, e biodisponibilidade, por forma a torná-los adequados à administração por via parentérica. Para além disso, as CDs podem ser utilizadas como componentes para a estrutura de sistemas injetáveis de libertação de fármacos mais complexos e com propriedades otimizadas, como nanopartículas e hidrogéis supramoleculares, que se têm mostrado particularmente vantajosos no transporte de fármacos anticancerígenos. Contudo, e apesar de que algumas CDs já se encontram aprovadas para uso em preparações parentéricas, apenas alguns tipos de CDs são considerados seguros para a administração por via parentérica. Deste modo, a aplicação das CDs no desenvolvimento de formulações parentéricas tem vindo a tornar-se uma prática mais comum nos últimos anos devido à aprovação global significativa pelas autoridade de saúde, o que estimula o desenvolvimento de sistemas injetáveis de libertação de fármacos mais seguros e eficazes.

This thesis deals primarily with supramolecular chemistry based on cucurbit[n]uril (CB[n], n = 7 and 8) host molecules. The research has been focused on the synthesis and characterization of host-guest complexes CB[n] with aromatic guest molecules, and the study of the effects of the host-guest complexation on the chemical reactivity and spectroscopic properties of the included guests, such as their photoreactivity and their UV-visible absorption and emission properties, in aqueous solution. The [4+4] photodimerization of protonated 2-aminopyridine (APH+) occurs stereoselectively to give the anti-trans product as the result of a preferred orientation of two APH+ guests in the cavity of CB[7]. The CB[7] host inhibits photohydration in the course of the photoisomerizations of protonated trans-1,2-bis(4-pyridyl)ethylene and trans-1,2-bis(1-methyl-4-pyridinium)ethylene by including the (4-pyridyl)ethylene portion of the guest, while this is not observed with trans-1,2-bis(1-hexyl-4-pyridinium)ethylene, as preferential inclusion of the hexyl groups leaves the vinyl group vulnerable to photohydration. Very strong CB[7] complexation of (E)-1-ferrocenyl-2-(1-methyl-4-pyridinium)ethylene completely inhibits the (E)→(Z) photoisomerization process. The H/D exchange rates and acidities of the C(2)-proton of cationic imidazolium and thiazolium (including thiamine and thiamine phosphates) carbon acids are decreased upon their complexation with CB[7]. Inclusion of protonated aromatic amines (and aromatic alcohols) in the cavity CB[7] significantly decreases their ground and excited state acidities, such that the emission is switched from the neutral amine to the protonated amine excited state, resulting in changes in the color of fluorescence. The fluorescence of acridizinium cations can be switched off by the formation of 2:1 complexes with CB[8] and then switched back on again by the addition of CB[7] or a competing guest molecule. The stabilization of the deep blue color of the 4,4’-bis(dimethylamino)diphenyl carbonium ion, upon complexation of the corresponding carbinol with CB[7], results from a complexation-induced shift in the carbinol/carbonium ion equilibrium. A dramatic purple to blue color change in pinacyanol chloride upon addition of CB[7] is due to a partial breakup of dye aggregates, upon the interactions of the dye with the host molecule. The CB[n] complexation-induced emission and/or absorption color switch have the potential to be employed in molecular switches and in chemical sensing.
Thesis (Ph.D, Chemistry) -- Queen's University, 2007-08-07 09:21:06.553

Tese de Doutoramento em Química, no ramo de Química Macromolecular, apresentada ao Departamento de Química da Faculdade de Ciências e Tecnologia da Universidade de Coimbra
The accurate description of the interaction patterns, energetics and binding affinities of host-guest systems by means of molecular dynamics (MD) and free-energy calculations have gained increasing interest in pharmaceutical technology and drug delivery applications. In spite of its importance, many conceptual and practical aspects are still under intense scrutiny, particularly those related to the molecular origin, strength, and individual/cooperative action of the driving forces governing soft associations in this type of systems. Relevant paradigms of such factors in understanding molecular recognition and binding, in inclusion complexes consisting of cyclic oligosaccharides , including cyclodextrins (Cds), or water-soluble glycoluril-based macrocycles, bambusurils (BUs), and guest molecules of different natures and sizes, are the critical roles of solvent, enthalpy, entropy and conformational contributions. The work described in this dissertation aims at developing a systematic modeling approach for understanding the factors that govern the formation of supramolecular nanostructures resorting to MD and potential of mean force calculations. The main topics gather different aspects in quantifying host-guest binding. Firstly, self-consistent algorithmic approaches for exploring conformational space and decomposing energy changes are developed and combined with the automated selection of representative molecular structures and inclusion/binding modes, providing the initial conformations for free-energy calculations. This input information is subsequently used for developing binding affinity models and introducing a broad picture on the structure and dynamics of several molecular systems, suitable as biocompatible platforms for drug delivery. These include (i) the prediction of the preferred binding modes and affinities, and the quantification of interaction and energy components guiding complex formation, in water, between β-Cd and several naphthalene (Np) derivatives, (ii) the assessment of the effect of guest size, host flexibility and cavity size in supramolecular complexation involving β- and γ-Cds and Np, adamantane (Ad) and lycorine derivatives, (iii) the establishment of thermodynamic signatures and identification of stabilizing/destabilizing noncovalent interaction within the complexes between hyaluronic acid bearing monomeric β-Cd and Ad moieties, used as models of network junction nodes, (iv) the description of the aggregation process, in water, between Cds in the absence and in the presence of hydrophobic or amphiphilic guests, and finally (v) the study of the caging ability of BUs to anions, also in aqueous media, to focus on a different type of complexes. It is shown that substitution of Np promotes an increase in the complexation constant (up to 100-fold), irrespective of the nature of the substituent. Entropy does not favor inclusion, being the order of magnitude of the binding free-energy given by the enthalpic component, with a dominating host-guest interaction contribution. Complexation is also governed by the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 10^4). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in the recognition phenomena. It corresponds to an increase in energy of up to ca. 90 kJ mol^-1. Complex stability and desolvation of the host cavity and guest backbone are related. Complexes with γ-Cd are generally less stable than those with γ-Cd, since deformation in γ-Cd opposes inclusion and binding. It is also observed that structural variations promote major changes in the thermodynamic variables. The presence of amphiphilic chains in both host and guest molecules emphasizes inclusion and drastically increases the binding constant (to ca. 10^28). In what pertains to β-Cd aggregation in water, it is concluded that β-Cds may form dimers with varying arrangements and proximities. The model guest, poly(vinyl alcohol) , promotes the formation of Cd dimers and contains both hydrophilic and hydrophobic groups that interact either with the outside part of Cds or form inclusion complexes. Finally, water-soluble BUs can bind and isolate inorganic anions in the center of the hydrophobic cavity, with high affinity and selectivity. The latter are hermetically sealed inside the cavity, as a result of a concerted action involving conformation and desolvation of both ion and BU cavity. Substantial modulation of the inclusion complexes, as well as the character of the network interaction sites and the formation of small aggregates, can thus be achieved imposing different features and arrangements. This has direct implications upon the design of supramolecular structures with tailored properties based on these complexes.
Uma descrição precisa e quantificação dos padrões de interação, incluindo energias e afinidades de ligação, dos sistemas hospedeiro-hóspede (H-G) por meio de dinâmica molecular (MD) e cálculos de energia livre têm ganhado um crescente interesse devido a aplicações em tecnologia farmacêutica e administração de fármacos. Apesar da sua importância, muitos aspetos conceptuais e práticos ainda estão sob intenso escrutínio, incluindo a origem molecular e a dualidade ação individual/cooperativa das forças que governam a associação neste tipo de sistemas. As contribuições do solvente, entalpia, entropia e conformação constituem paradigmas relevantes de tais fatores em complexos de inclusão com oligossacarídeos cíclicos, incluindo ciclodextrinas (Cds) ou macrociclos constituidos por grupos glicoluril, os bambusurilos (BUs), e moléculas hóspede (G) de diferentes naturezas e tamanhos. O trabalho descrito nesta dissertação visa desenvolver uma modelação sistemática para compreender os fatores que governam a formação de nanoestruturas supramoleculares baseadas em complexos H-G, recorrendo à MD e a cálculos de potencial de força média. O foco principal tem a ver com a quantificação da ligação H-G. São desenvolvidas abordagens algorítmicas auto-consistentes para explorar o espaço conformacional e diferenças de energia em termos resultantes de decomposição sistemática em componentes energéticas relevantes. Estas resultam de uma combinação com uma seleção automatizada de estruturas moleculares representativas e imposição dos modos de inclusão/ligação, fornecendo as conformações iniciais. Estas informações de entrada são usadas para desenvolver modelos de afinidade de ligação e descrever a estrutura e dinâmica de vários sistemas moleculares, adequados como plataformas biocompatíveis para administração de fármacos. As aplicações incluem (i) a previsão dos modos e afinidades de ligação, e a quantificação de componentes de interação e energia que estabelecem a formação do complexo, em água, entre β-Cds e vários derivados de naftaleno (Np) contendo diferentes substituintes, (ii) a avaliação do efeito do tamanho de Gs, da flexibilidade do H e do tamanho da cavidade na complexação supramolecular, envolvendo derivados β- e γ-Cds, e Np, adamantano (Ad) e licorina, (iii) o estabelecimento de grandezas termodinâmicas relevantes e a identificação de interações estabilizantes/destabilizantes dentro dos complexos entre derivados de ácido hialurónico modificados com β-Cd e Ad, usados como modelos de pontos de junção em redes transientes, (iv) a descrição do processo de agregação, em água, entre Cds na ausência e na presença de Gs hidrofóbicos ou anfifílicos, e finalmente, (v) inspecionar a capacidade de fixação de aniões em BUs, também em meio aquoso, para tornar mais amplo o leque de aplicações. Mostra-se que a substituição do Np promove um aumento na constante de complexação (até 100 vezes), independentemente da natureza do substituinte. A entropia não favorece a inclusão, sendo a ordem de grandeza da energia livre de ligação dada pelo componente entálpico, com uma contribuição dominante da interação H-G. A complexação é também afetada pelo volume disponível na cavidade da Cd, promovendo variações na adaptação de moléculas Gs e observando-se uma penalização resultante da entalpia de deformação de Cd nas constantes de ligação (que podem diminuir até um fator de 10^4 ). A deformação da Cd, tantas vezes negligenciada, desempenha, assim, um papel importante no comportamento de interação de sistemas baseados em Cd de cavidades maiores, sendo crucial em fenómenos associados de reconhecimento molecular. Nos sistemas estudados, pode penalizar a energia de associação até ca. 90 kJ mol^−1 . A distorção não é tão significativa na β-Cd, onde Gs de maiores dimensões promovem constantes de ligação mais elevadas. A estabilidade do complexo está relacionada com a dessolvatação da cavidade do H e do G. Complexos com γ-Cd são geralmente menos estáveis do que aqueles com β-Cd, já que a deformação em γ-Cd se opõe à inclusão e à ligação. Observa-se também que variações estruturais promovem grandes mudanças nas variáveis termodinâmicas. A presença de cadeias anfifílicas nas moléculas H e G enfatiza a inclusão e aumenta drasticamente a constante de ligação (até valores de 10^28 ). No que diz respeito à agregação de β-Cd em água, conclui-se que estas moléculas podem formar dímeros com arranjos e proximidades variáveis. Utilizando Álcool polivinílico como G, verifica-se que este promove a formação de dímeros de Cd, e que contém grupos hidrofílicos e hidrofóbicos que interagem com a parte externa de Cds ou formam complexos de inclusão. Finalmente, BUs solúveis em água podem incluir e isolar aniões inorgânicos no centro da cavidade hidrofóbica, com alta afinidade e seletividade. Estes últimos podem ser hermeticamente selados dentro da cavidade, como resultado de uma ação concertada envolvendo modificação na conformação e dessolvatação do ião e da cavidade do BU. A modulação de complexos de inclusão, controlando a estabilidade dos sítios de interação numa rede transiente e a formação de pequenos agregados, pode ser alcançada impondo diferentes substituições e arranjos. Tal tem implicações diretas no projeto racional de estruturas supramoleculares baseadas nestes complexos.