An Ultra‐Long‐Lived Triplet Excited State in Water at Room Temperature: Insights on the Molecular Design of Tridecafullerenes

Suitably engineered molecular systems exhibiting triplet excited states with very long lifetimes are important for high-end applications in nonlinear optics, photocatalysis, or biomedicine. We report the finding of an ultra-long-lived triplet state with a mean lifetime of 93 ms in an aqueous phase at room temperature, measured for a globular tridecafullerene with a highly compact glycodendrimeric structure. A series of three tridecafullerenes bearing different glycodendrons and spacers to the C60 units have been synthesized and characterized. UV/Vis spectra and DLS experiments confirm their aggregation in water. Steady-state and time-resolved fluorescence experiments suggest a different degree of inner solvation of the multifullerenes depending on their molecular design. Efficient quenching of the triplet states by O2 but not by waterborne azide anions has been observed. Molecular modelling reveals dissimilar access of the aqueous phase to the internal structure of the tridecafullerenes, differently shielded by the glycodendrimeric shell

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A hard copy is available in UCD Library at GEN 330.08 IR/UN

Artificial and natural photosensitizers in Photodynamic Therapy: Expanded porphycene conjugates and hypericin

Aquesta tesi presenta l’estudi d’aplicacions antimicrobianes i antineoplàstiques de conjugats 2-aminotiazoloporificè i d’hipericina en teràpia fotodinàmica (TFD), tot intentant entendre el mecanisme d’acció. La conjugació de 9-isotiocianat-2,7,12,17-metoxietilporficè a dues entitats hidrofíliques, l’antibiòtic gentamicina i el catió lipofílic trifenilfosfoni, formen compostos amfifílics amb gran activitat biològica contra microorganismes i cèl·lules HeLa. La conjugació presenta un sistema aromàtic dual, amb gran absorció al vermell i amb alts rendiments d’oxigen singlet. La seva fluorescència, tot i ser tènue, ha estat utilitzada en aplicacions com la microscòpia confocal i fins i tot en microscòpia de super-resolució d’emissió estimulada (STED). El conjugat amb Gentamicina és capaç d’inactivar S. aureus, E. coli i C. albicans en el rang submicromolar, però sense la selectivitat buscada doncs també inactiva cèl·lules canceroses. El conjugat amb el catió Trifenilfosfoni presenta una menor activitat en microorganismes que el conjugat anterior, però més elevat en càncer degut a una localització subcel·lular parcialment dirigida cap a mitocondris. La Hipericina, per altra banda, és un conegut i potent fotosensibilitzador natural que és costós d’obtenir tant purificant un extracte de planta com la seva síntesi química. En aquest sentit, s’ha comparat un extracte hidroalcòholic liofilitzat de H. perforatum sense purificar amb hipericina pura, observant com les seves propietats fotofísiques no es veuen mitigades per altres productes en l’extracte i com la seva activitat contra S. aureus és preservada. Seguint amb la Hipericina, àcid retinoic ha estat incorporat al complex β-lactoglobulina-hipericina prèviament descrit per avaluar el seu potencial en assajos antimicrobians in vitro. Tot i ser un mitigador d’oxigen singlet, aquesta adició no afecta al rendiment de la Hipericina contra S. aureus, demostrant així el potencial del complex per alliberar dos fàrmacs simultàniament en tractar acne vulgaris: la hipericina per tractar infeccions i l’àcid retinoic per calmar la inflamació.Esta tesis presenta el estudio de aplicaciones antimicrobianas y antineoplásticas de conjugados 2-aminotiazoloporficenos e Hipericina en terapia fotodinámica, procurando entender su mecanismo de acción. La conjugación de 9-isotiocianato-2,7,12,17-metoxietilporficeno con dos entidades hidrofílicas, el antibiótico gentamicina y el catión lipofílico trifenilfosfonio, forma compuestos anfifílicos con gran actividad biológica contra microorganismos y células HeLa. Los conjugados presentan un sistema aromático dual, gran absorción en el rojo y altos rendimientos de oxígeno singlete. Su fluorescencia, pese a ser débil, ha sido usada en aplicaciones como la microscopía confocal e incluso en microscopía de super-resolución de emisión estimulada (STED). El conjugado de Gentamicina es capaz de inactivar S. aureus, E. coli y C. albicans en el rango submicromolar, pero sin la selectividad buscada ya que también inactiva células cancerígenas. El conjugado de trifenilfosfonio presenta menos actividad que el conjugado anterior en microorganismos, pero mayor en cáncer debido a una sublocalización celular parcialmente dirigida hacia mitocondrias. La Hipericina, por otro lado, es un conocido y potente fotosensibilizador natural que es costoso de obtener ya sea purificando extractos naturales de plantes o mediante síntesis. En este aspecto, se ha comparado un extracto hidroalcohólico liofilizado sin purificar de H. perforatum con Hipericina pura, observando como las propiedades fotofísicas no se ven mitigadas debido a la presencia de otros compuestos en el extracto y preservando su actividad contra S. aureus. Siguiendo con Hipericina, ácido retinoico ha sido añadido al complejo β-lactoglobulina-hipericina previamente descrito para probar su potencial actividad antimicrobiana in vitro. Pese a ser un mitigador de oxígeno singlete, la adición de ácido retinoico no afecta al rendimiento de la Hipericina contra S. aureus, demostrando el potencial del complejo para liberar dos fármacos simultáneamente para tractar acne vulgaris: la hipericina para tratar la infección y el ácido retinoico para calmar la inflamación.This thesis reports the study of antimicrobial and antineoplastic applications of novel 2-aminothiazolo porphycene conjugates and Hypericin in Photodynamic therapy (PDT), while aiming to understand their mechanism of action. The conjugation of 9-isothiocyanate-2,7,12,17-methoxyethylporphycene to two hydrophilic entities, gentamicin as an antibiotic and triphenylphosphonium as a lipophilic cation, rendered amphiphilic compounds with high biological activity against microorganisms and HeLa cells. The conjugates presented dual aromatic systems, highly absorbing in the deep red with high singlet oxygen yields. Their fluorescence, despite being dim, was still exploited in applications such as confocal microscopy and even stimulated emission depletion super-resolution microscopy (STED). The Gentamicin conjugate was able to inactivate S. aureus, E. coli and C. albicans in the submicromolar range, but lacking the intended selectivity since it also inactivates cancer cells. The conjugate endowed with the Triphenylphosphonium cation presented less activity against microorganisms than the previous conjugate, but higher for cancer PDT due to the partial subcellular localization guidance towards mitochondria. Hypericin, on the other hand, is a powerful and well-known naturally occurring photosensitizer which is costly to both purify from a plant extract or chemically synthesized. In this regard, a non-purified lyophilized hydroalcoholic H. perforatum extract was compared with pure hypericin, observing how its photophysical properties are not quenched by other compounds in the extract and that its antimicrobial activity against S. aureus was preserved. Continuing with Hypericin, retinoic acid was incorporated into the previously reported β-lactoglobulin-Hypericin complex in order to test its antimicrobial in vitro potential. Despite being a singlet oxygen quencher, this addition did not affect the Hypericin’s performance against S. aureus, proving its potential as a double payload vehicle when treating acne vulgaris: Hypericin to treat infections and the retinoid to calm inflammation.Questa tesi riguarda lo studio di applicazioni antimicrobiche e antineoplastiche di nuovi coniugati di 2-aminotiazoloporficeno e dell’Ipericina nella terapia fotodinamica (TFD), con l'obiettivo di comprendere il loro meccanismo d'azione. La coniugazione del 9-isotiocianato-2,7,12,17-metossietilporficeno in due entitá idrofiliche, con gentamicina come antibiotico e trifenilfosfonio come catione lipofilo, ha reso composti anfifilici con elevata attività biologica contro i microrganismi e le cellule HeLa. I coniugati presentavano sistemi aromatici doppi, altamente assorbenti nel rosso lontano con una alta resa di ossigeno singoletto. La loro fluorescenza, nonostante fosse debole, è stata tuttavia utilizzata in applicazioni come la Microscopia Confocale e persino nella Microscopia di svuotamento dell'emissione stimolata (STED). Il coniugato di gentamicina è stato in grado di inattivare S. aureus, E. coli e C. albicans nell’intervallo di concentrazioni del submicromolare, ma si è rivelato carente nella selettività voluta poiché inattiva anche le cellule tumorali. Il coniugato fornito del catione trifenilfosfonio presentava minor attività contro i microrganismi rispetto al coniugato precedente, ma un’attivitá maggiore contro il cancro a causa del parziale indirizzamento con localizzazione subcellulare nei i mitocondri. L'ipericina, d'altra parte, è un ben noto fotosensibilizzatore naturale e potente, costoso sia se ottenuto per purificazione da un estratto di piante, sia se sintetizzato chimicamente. A questo proposito, un estratto liofilizzato idroalcolico di H. perforatum non purificato è stato confrontato con l'ipericina pura, osservando come le sue proprietà fotofisiche non siano soppresse da altri composti nell'estratto e come sia preservata la sua attività antimicrobica contro S. aureus. Continuando con l'ipericina, l'acido retinoico è stato incorporato nel complesso β-lattoglobulina-ipericina precedentemente riportato per esaminare il suo potenziale antimicrobico in vitro. Nonostante sia un soppressore di ossigeno singoletto, questa aggiunta non ha avuto impatto sull’efficacia dell'ipericina contro S. aureus, dimostrando il suo potenziale come doppio agente nella cura dell'acne vulgaris: l'ipericina per le infezioni e l’acido retinoico per calmare l'infiammazione

Impact of taxation on financial servies

A hard copy is available in UCD Library at GEN 330.08 IR/UN

Artificial and natural photosensitizers in Photodynamic Therapy: Expanded porphycene conjugates and hypericin

Aquesta tesi presenta l’estudi d’aplicacions antimicrobianes i antineoplàstiques de conjugats 2-aminotiazoloporificè i d’hipericina en teràpia fotodinàmica (TFD), tot intentant entendre el mecanisme d’acció. La conjugació de 9-isotiocianat-2,7,12,17-metoxietilporficè a dues entitats hidrofíliques, l’antibiòtic gentamicina i el catió lipofílic trifenilfosfoni, formen compostos amfifílics amb gran activitat biològica contra microorganismes i cèl·lules HeLa. La conjugació presenta un sistema aromàtic dual, amb gran absorció al vermell i amb alts rendiments d’oxigen singlet. La seva fluorescència, tot i ser tènue, ha estat utilitzada en aplicacions com la microscòpia confocal i fins i tot en microscòpia de super-resolució d’emissió estimulada (STED). El conjugat amb Gentamicina és capaç d’inactivar S. aureus, E. coli i C. albicans en el rang submicromolar, però sense la selectivitat buscada doncs també inactiva cèl·lules canceroses. El conjugat amb el catió Trifenilfosfoni presenta una menor activitat en microorganismes que el conjugat anterior, però més elevat en càncer degut a una localització subcel·lular parcialment dirigida cap a mitocondris. La Hipericina, per altra banda, és un conegut i potent fotosensibilitzador natural que és costós d’obtenir tant purificant un extracte de planta com la seva síntesi química. En aquest sentit, s’ha comparat un extracte hidroalcòholic liofilitzat de H. perforatum sense purificar amb hipericina pura, observant com les seves propietats fotofísiques no es veuen mitigades per altres productes en l’extracte i com la seva activitat contra S. aureus és preservada. Seguint amb la Hipericina, àcid retinoic ha estat incorporat al complex β-lactoglobulina-hipericina prèviament descrit per avaluar el seu potencial en assajos antimicrobians in vitro. Tot i ser un mitigador d’oxigen singlet, aquesta adició no afecta al rendiment de la Hipericina contra S. aureus, demostrant així el potencial del complex per alliberar dos fàrmacs simultàniament en tractar acne vulgaris: la hipericina per tractar infeccions i l’àcid retinoic per calmar la inflamació.Esta tesis presenta el estudio de aplicaciones antimicrobianas y antineoplásticas de conjugados 2-aminotiazoloporficenos e Hipericina en terapia fotodinámica, procurando entender su mecanismo de acción. La conjugación de 9-isotiocianato-2,7,12,17-metoxietilporficeno con dos entidades hidrofílicas, el antibiótico gentamicina y el catión lipofílico trifenilfosfonio, forma compuestos anfifílicos con gran actividad biológica contra microorganismos y células HeLa. Los conjugados presentan un sistema aromático dual, gran absorción en el rojo y altos rendimientos de oxígeno singlete. Su fluorescencia, pese a ser débil, ha sido usada en aplicaciones como la microscopía confocal e incluso en microscopía de super-resolución de emisión estimulada (STED). El conjugado de Gentamicina es capaz de inactivar S. aureus, E. coli y C. albicans en el rango submicromolar, pero sin la selectividad buscada ya que también inactiva células cancerígenas. El conjugado de trifenilfosfonio presenta menos actividad que el conjugado anterior en microorganismos, pero mayor en cáncer debido a una sublocalización celular parcialmente dirigida hacia mitocondrias. La Hipericina, por otro lado, es un conocido y potente fotosensibilizador natural que es costoso de obtener ya sea purificando extractos naturales de plantes o mediante síntesis. En este aspecto, se ha comparado un extracto hidroalcohólico liofilizado sin purificar de H. perforatum con Hipericina pura, observando como las propiedades fotofísicas no se ven mitigadas debido a la presencia de otros compuestos en el extracto y preservando su actividad contra S. aureus. Siguiendo con Hipericina, ácido retinoico ha sido añadido al complejo β-lactoglobulina-hipericina previamente descrito para probar su potencial actividad antimicrobiana in vitro. Pese a ser un mitigador de oxígeno singlete, la adición de ácido retinoico no afecta al rendimiento de la Hipericina contra S. aureus, demostrando el potencial del complejo para liberar dos fármacos simultáneamente para tractar acne vulgaris: la hipericina para tratar la infección y el ácido retinoico para calmar la inflamación.This thesis reports the study of antimicrobial and antineoplastic applications of novel 2-aminothiazolo porphycene conjugates and Hypericin in Photodynamic therapy (PDT), while aiming to understand their mechanism of action. The conjugation of 9-isothiocyanate-2,7,12,17-methoxyethylporphycene to two hydrophilic entities, gentamicin as an antibiotic and triphenylphosphonium as a lipophilic cation, rendered amphiphilic compounds with high biological activity against microorganisms and HeLa cells. The conjugates presented dual aromatic systems, highly absorbing in the deep red with high singlet oxygen yields. Their fluorescence, despite being dim, was still exploited in applications such as confocal microscopy and even stimulated emission depletion super-resolution microscopy (STED). The Gentamicin conjugate was able to inactivate S. aureus, E. coli and C. albicans in the submicromolar range, but lacking the intended selectivity since it also inactivates cancer cells. The conjugate endowed with the Triphenylphosphonium cation presented less activity against microorganisms than the previous conjugate, but higher for cancer PDT due to the partial subcellular localization guidance towards mitochondria. Hypericin, on the other hand, is a powerful and well-known naturally occurring photosensitizer which is costly to both purify from a plant extract or chemically synthesized. In this regard, a non-purified lyophilized hydroalcoholic H. perforatum extract was compared with pure hypericin, observing how its photophysical properties are not quenched by other compounds in the extract and that its antimicrobial activity against S. aureus was preserved. Continuing with Hypericin, retinoic acid was incorporated into the previously reported β-lactoglobulin-Hypericin complex in order to test its antimicrobial in vitro potential. Despite being a singlet oxygen quencher, this addition did not affect the Hypericin’s performance against S. aureus, proving its potential as a double payload vehicle when treating acne vulgaris: Hypericin to treat infections and the retinoid to calm inflammation.Questa tesi riguarda lo studio di applicazioni antimicrobiche e antineoplastiche di nuovi coniugati di 2-aminotiazoloporficeno e dell’Ipericina nella terapia fotodinamica (TFD), con l'obiettivo di comprendere il loro meccanismo d'azione. La coniugazione del 9-isotiocianato-2,7,12,17-metossietilporficeno in due entitá idrofiliche, con gentamicina come antibiotico e trifenilfosfonio come catione lipofilo, ha reso composti anfifilici con elevata attività biologica contro i microrganismi e le cellule HeLa. I coniugati presentavano sistemi aromatici doppi, altamente assorbenti nel rosso lontano con una alta resa di ossigeno singoletto. La loro fluorescenza, nonostante fosse debole, è stata tuttavia utilizzata in applicazioni come la Microscopia Confocale e persino nella Microscopia di svuotamento dell'emissione stimolata (STED). Il coniugato di gentamicina è stato in grado di inattivare S. aureus, E. coli e C. albicans nell’intervallo di concentrazioni del submicromolare, ma si è rivelato carente nella selettività voluta poiché inattiva anche le cellule tumorali. Il coniugato fornito del catione trifenilfosfonio presentava minor attività contro i microrganismi rispetto al coniugato precedente, ma un’attivitá maggiore contro il cancro a causa del parziale indirizzamento con localizzazione subcellulare nei i mitocondri. L'ipericina, d'altra parte, è un ben noto fotosensibilizzatore naturale e potente, costoso sia se ottenuto per purificazione da un estratto di piante, sia se sintetizzato chimicamente. A questo proposito, un estratto liofilizzato idroalcolico di H. perforatum non purificato è stato confrontato con l'ipericina pura, osservando come le sue proprietà fotofisiche non siano soppresse da altri composti nell'estratto e come sia preservata la sua attività antimicrobica contro S. aureus. Continuando con l'ipericina, l'acido retinoico è stato incorporato nel complesso β-lattoglobulina-ipericina precedentemente riportato per esaminare il suo potenziale antimicrobico in vitro. Nonostante sia un soppressore di ossigeno singoletto, questa aggiunta non ha avuto impatto sull’efficacia dell'ipericina contro S. aureus, dimostrando il suo potenziale come doppio agente nella cura dell'acne vulgaris: l'ipericina per le infezioni e l’acido retinoico per calmare l'infiammazione

Crosswise Phthalocyanines with Collinear Functionalization: New Paradigmatic Derivatives for Efficient Singlet Oxygen Photosensitization

This is the peer reviewed version of the following article: Revuelta‐Maza, M. A., Hally, C., Nonell, S., de la Torre, G., & Torres, T. (2019). Crosswise Phthalocyanines with Collinear Functionalization: New Paradigmatic Derivatives for Efficient Singlet Oxygen Photosensitization. ChemPlusChem, 84(6), 673-679, which has been published in final form at https://doi.org/10.1002/cplu.201800631. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsSupporting information for this article is available on the WWW under https://doi.org/10.1002/cplu.201800631We describe here the preparation of a series of trans-ABAB Zn(II) phthalocyanines (ZnPcs, which combine several interesting features. First, these compounds present high solubility and hindered aggregation, due to the functionalization of two facing isoindole constituents (B) of the ZnPc with bis(trifluoromethylphenyl) units. Second, the other two isoindoles (A) bear extra-annulated phthalimide units containing different substituents in the nitrogen positions, this feature results in a collinear arrangement of a variety of functional groups. Some of these collinearly functionalized ZnPcs are interesting building blocks for constructing either homo- or heteroarrays containing ZnPc units. Furthermore, the amphiphilic nature of some members of the series renders them interesting candidates for photosensitization of singlet oxygen. Photophysical studies on a model compound of the series have shown that these molecules are efficient singlet oxygen photosensitizers in both polar and apolar media, with 1O2 quantum yields (φΔ) as high as 0.74This work has been supported by MINECO, Spain (CTQ2017‐85393‐P and CTQ2016‐78454‐C2‐1‐R). C. H. thanks the European Social Funds and the SUR del DEC de la Generalitat de Catalunya for his predoctoral fellowships (Grant No. 2017 FI_B 00617 and 2018 FI_B1 00174

A porphycene-gentamicin conjugate for enhanced photodynamic inactivation of bacteria

A novel photoantimicrobial agent, namely 2-aminothiazolo[4,5-c]-2,7,12,17-tetrakis(methoxyethyl)porphycene (ATAZTMPo-gentamicin) conjugate, has been prepared by a click reaction between the red-light absorbing 9-isothiocyanate-2,7,12,17-tetrakis(methoxyethyl)porphycene (9-ITMPo) and the antibiotic gentamicin. The conjugate exhibits submicromolar activity in vitro against both Gram-positive and Gram-negative bacteria (Staphylococcus aureus and Escherichia coli, respectively) upon exposure to red light and is devoid of any cytotoxicity in the dark. The conjugate outperforms the two components delivered separately, which may be used to enhance the therapeutic index of gentamicin, broaden the spectrum of pathogens against which it is effective and reduce its side effects. Additionally, we report a novel straightforward synthesis of 2,7,12,17-tetrakis(methoxyethyl) porphycene (TMPo) that decreases the number of steps from nine to six

Fluorine-substituted tetracationic ABAB-phthalocyanines for efficient photodynamic inactivation of Gram-positive and Gram-negative bacteria

Herein, we report the synthesis and characterization of new amphiphilic phthalocyanines (Pcs), the study of their singlet oxygen generation capabilities, and biological assays to determine their potential as photosensitizers for photodynamic inactivation of bacteria. In particular, Pcs with an ABAB geometry (where A and B refer to differently substituted isoindole constituents) have been synthesized. These molecules are endowed with bulky bis(trifluoromethylphenyl) groups in two facing isoindoles, which hinder aggregation and favour singlet oxygen generation, and pyridinium or alkylammonium moieties in the other two isoindoles. In particular, two water-soluble Pc derivatives (PS-1 and PS-2) have proved to be efficient in the photoinactivation of S. aureus and E. coli, selected as models of Gram-positive and Gram-negative bacteriaThis work has been supported by MINECO, Spain (CTQ2017-85393-P and CTQ2016-78454-C2-1-R

A Double Payload Complex between Hypericin and All-<em>trans</em> Retinoic Acid in the β-Lactoglobulin Protein

Combined therapies are usually used to treat acne vulgaris since this approach can tackle various foci simultaneously. Using a combination of spectroscopic, computational, and microbiological techniques and methods, herein we report on the use of β-lactoglobulin as a double payload carrier of hypericin (an antimicrobial photodynamic agent) and all-trans retinoic acid (an anti-inflammatory drug) for S. aureus in vitro photodynamic inactivation. The addition of all-trans retinoic acid to hypericin-β-lactoglobulin complex renders a photochemically safe vehicle due to the photophysical quenching of hypericin, which recovers its photodynamic activity when in contact with bacteria. The ability of hypericin to photoinactivate S. aureus was not affected by retinoic acid. β-Lactoglobulin is a novel biocompatible and photochemically safe nanovehicle with strong potential for the treatment of acne