Photocatalytic Aerobic Dehydrogenation of N-Heterocycles with Ir(III) Photosensitizers Bearing the 2(2′-Pyridyl)benzimidazole Scaffold

Photoredox catalysis constitutes a very powerful tool in organic synthesis, due to its versatility, efficiency, and the mild conditions required by photoinduced transformations. In this paper, we present an efficient and selective photocatalytic procedure for the aerobic oxidative dehydrogenation of partially saturated N-heterocycles to afford the respective N-heteroarenes (indoles, quinolines, acridines, and quinoxalines). The protocol involves the use of new Ir(III) biscyclometalated photocatalysts of the general formula [Ir(C^N)2(N^N′)]Cl, where the C^N ligand is 2- (2,4-difluorophenyl)pyridinate, and N^N′ are different ligands based on the 2-(2′-pyridyl)benzimidazole scaffold. In-depth electrochemical and photophysical studies as well as DFT calculations have allowed us to establish structure−activity relationships, which provide insights for the rational design of efficient metal-based dyes in photocatalytic oxidation reactions. In addition, we have formulated a dual mechanism, mediated by the radical anion superoxide, for the above-mentioned transformations.We acknowledge the financial support provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI2018- 100709-B-C21 and CTQ (QMC)-RED2018-102471-T), Consejería de Educación de la Junta de Castilla y León and FEDER (BU087G19 and BU067P20), and Junta de Comunidades de Castilla-La Mancha-FEDER (JCCM) (grant SBPLY/19/ 180501/000260). I.E. acknowledges his fellowship to both the European Social Fund and Consejería de Educación de la Junta de Castilla y León (EDU/1100/2017). We are also indebted to J. Delgado, P. Castroviejo, and M. Mansilla (PCT of the Universidad de Burgos) for technical support, G. GarcíaHerbosa for providing us access to CV equipment, and J. V. Cuevas-Vicario for support with Gaussian

Rational design of mitochondria targeted thiabendazole-based Ir(III) biscyclometalated complexes for a multimodal photodynamic therapy of cancer

Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)2(N^N′ )]Cl (N^N′ = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and [3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action, which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both processes seem to be the result of photocatalytic oxidation processes.We acknowledge the financial support provided by the Spanish Ministerio de Ciencia, Innovacion ´ y Universidades (RTI2018-100709-BC21, RTI2018-100709-B-C22) and CTQ (QMC)-RED2018-102471-T), Junta de Castilla y Leon ´ (BU087G19), Junta de Comunidades de CastillaLa Mancha-FEDER (JCCM) (grant SBPLY/19/180501/000260) and UCLM-FEDER (grants 2019-GRIN-27183 and 2019-GRIN-27209). I. Echevarría wants to acknowledge his fellowship to both the European Social Fund and Consejería de Educacion ´ de la Junta de Castilla y Leon ´ (EDU/1100/2017). E. Zafon wants to acknowledge her predoctoral fellowship to the Generalitat de Catalunya (AGAUR; 2021 FI_B 01036). We are also indebted to Jacinto Delgado, Pilar Castroviejo and Marta Mansilla (PCT of the Universidad de Burgos) for technical support and Jos´e Vicente Cuevas Vicario for advice and support with theoretical calculations and Gabriel García-Herbosa for providing us access to CV equipment

Synthesis and characterization of Ru(II), Ir(III) and Rh(III) trischelate complexes with benzimidazole based ligands for photodynamic therapy and photocatalysis: the bright side of the chemistry

En la siguiente tesis se detalla el trabajo de investigación realizado en la síntesis y caracterización de compuestos tris-quelato de Ru(II), Ir(III) y Rh(III) con ligandos basados en benzimidazoles, para su uso en dos campos, la terapia fotodinámica o PDT (por sus siglas en inglés), y la fotocatálisis. Se ha escogido usar estos metales y ligandos por sus conocidas propiedades farmacológicas y fotofísicas, que los convierte en una opción de interés para ambos campos de aplicación. Cabe resaltar, el interés de estas áreas de estudio, siendo la PDT una terapia contra el cáncer con las ventajas de permitir un preciso control espacio-temporal e inhibir los mecanismos de resistencia a los fármacos que a menudo poseen las células cancerígenas. Y la fotocatálisis, una variante de la catálisis tradicional que usa la luz visible como fuente de energía, posibilitando llevar a cabo las reacciones en condiciones suaves y medioambientalmente benignas.The following thesis details the research work carried out in the synthesis and characterization of tris-chelate compounds of Ru(II), Ir(III) and Rh(III) with ligands based on benzimidazoles, for use in two fields, photodynamic therapy or PDT, and photocatalysis. The election of these metals and ligands has been made due to their well-known pharmacological and photophysical properties, which makes them an interesting option for both fields of application. It is worth highlighting the interest of these areas of study, being PDT an anticancer therapy with the advantages of allowing an accurate space-time control and inhibiting the drug resistance mechanisms often presented by the cancer cells. And the photocatalysis, a variant of traditional catalysis that uses visible light as an energy source, making possible to carry out reactions in mild and environmentally benign conditions

Golgi-localized putative S-adenosyl methionine transporters required for plant cell wall polysaccharide methylation.

Polysaccharide methylation, especially that of pectin, is a common and important feature of land plant cell walls. Polysaccharide methylation takes place in the Golgi apparatus and therefore relies on the import of S-adenosyl methionine (SAM) from the cytosol into the Golgi. However, so far, no Golgi SAM transporter has been identified in plants. Here we studied major facilitator superfamily members in Arabidopsis that we identified as putative Golgi SAM transporters (GoSAMTs). Knockout of the two most highly expressed GoSAMTs led to a strong reduction in Golgi-synthesized polysaccharide methylation. Furthermore, solid-state NMR experiments revealed that reduced methylation changed cell wall polysaccharide conformations, interactions and mobilities. Notably, NMR revealed the existence of pectin 'egg-box' structures in intact cell walls and showed that their formation is enhanced by reduced methyl esterification. These changes in wall architecture were linked to substantial growth and developmental phenotypes. In particular, anisotropic growth was strongly impaired in the double mutant. The identification of putative transporters involved in import of SAM into the Golgi lumen in plants provides new insights into the paramount importance of polysaccharide methylation for plant cell wall structure and function.The characterisation of gosamt mutants was supported as part of The Center for Lignocellulose Structure and Formation, an Energy Frontier Research Center funded by the U.S. Department of Energy (DOE), Office of Science, Basic Energy Sciences (BES), under Award # DE-SC0001090. This study made use of NMR spectrometers at the MIT-Harvard Center for Magnetic Resonance, which is supported by NIH grant P41 GM132079. Initial gene identification, mutant isolation and preliminary pectin methylation studies were done by H.T. and P.D. under grant EPSRC/BBSRC OpenPlant (BB/L014130/1) and A.O., J.P.P-R and S.S-A supported by Fondo de Areas Prioritarias- Centro de Regulacion del Genoma-15090007, FONDECYT 1190695 and FONDECYT 1201467. Most of the microscopy experiments made use of The Sainsbury Laboratory Microscopy Core Facility which is supported by the Gatsby Charitable Foundation