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

Non-emissive RuII Polypyridyl Complexes as Efficient and Selective Photosensitizers for the Photooxidation of Benzylamines

RTI2018-100709-B-C21 CTQ (QMC)-RED2018-102471-T) Junta de Castilla y Leon (BU087G19 FEDER (BU042U16-BU305P18).Five new RuII polypyridyl complexes bearing N-(arylsulfonyl)-8-amidoquinolate ligands and three of their biscyclometalated IrIII congeners have been prepared and employed as photocatalysts (PCs) in the photooxidation of benzylamines with O2. In particular, the new RuII complexes do not exhibit photoluminescence, rather they harvest visible light efficiently and are very stable in solution under irradiation with blue light. Their non-emissive behavior has been related to the low electrochemical energy gaps and rationalized on the basis of theoretical calculations (DFT analysis) that predict low S0←T1 energy values. Moreover, the RuII complexes, despite being non-emissive, display excellent activities in the selective photocatalytic transformation of benzylamines into the corresponding imines. The presence of an electron-withdrawing group (-CF3) on the arene ring of the N-(arylsulfonyl)-8-amidoquinolate ligand improves the photocatalytic activity of the corresponding photocatalyst. Furthermore, all the experimental evidence, including transient absorption spectroscopy measurements suggest that singlet oxygen is the actual oxidant. The IrIII analogues are considerably more photosensitive and consequently less efficient photosensitizers (PSs).authorsversionpublishe

Exploiting the potential of autophagy in cisplatin therapy: a new strategy to overcome resistance

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach

Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach.This work was supported by grants from Fundación Leticia Castillejo Castillo and Ministerio de Economía y Competitividad (grant SAF2012-30862 to RSP and grant CTQ2011-24434 to FAJ). RSP Research Institute, and the work carried out in his laboratory receive support from the European Community through the regional development funding program (FEDER). JGC received funding from the Regional Ministry of Education and Science of Castilla–La Mancha (FPI-JCCM) and from Fundación Leticia Castillejo Castillo. MCC and RSP have a contract from the INCRECYT progra

Luminescent cyclometalated platinum compounds with N, P, and O^O ligands: Density-functional theory studies and analysis of the anticancer potential

Luminescent platinum cyclometalated complexes are species of interest mainly due to their applications in the optoelectronic and biological fields, especially with regard to their anticancer activity. Given this level of interest, a series of cyclometalated (2-[2′-thienyl]pyridinate, thpy and 2-[2,4-difluorophenyl]pyridinate, dfppy) platinum complexes with N-donor, PTA (1,3,5-triaza-7-phosphaadamantane) or chrysin-derived ligands (incorporating piperidine, HL1, or morpholine, HL2, fragments) were synthesized. The complexes are luminescent with tunable emission wavelengths. Aggregation in solution was observed for [Pt(dfppy)L1], 5. Density-functional theory (DFT) studies provided descriptions of the highest occupied molecular orbital (HOMO) and least unoccupied molecular orbital (LUMO) characteristics and their influence on the photophysical properties. The orbitals of 5–6 were different in nature to those of 1–4. Time-dependent DFT (TD-DFT) calculations showed that for 1–4 the excited states S1 and T1 reflect metal-to-ligand charge transfer (MLCT) and ligand-centered (LC) (C^N) contributions while for 5–6 these states are an LC transition centered on L1 or L2. The speciation in DMSO and DMSO/H2O was evaluated. Biological studies showed that [Pt(thpy)Cl(Hthpy)], 1, [Pt(dfppy)Cl(Hdfppy)], 2, and 5 exert significant cytotoxic activity against human cervical (HeLa) and lung (A549) carcinoma cells. The cytotoxicity of 1 increased 2.84-fold upon irradiation (blue). Microscopy assays on 5 showed that this compound accumulates in cytoplasmic organelles, preferentially in mitochondria. Mitochondrial metabolism was disrupted by the activity of the complexes, leading to a decline in the adenosine triphosphate (ATP) cellular content. Overall, the results show an alternative anticancer activity for complexes 1, 2, and 5, which could be of great interest for the treatment of tumors with acquired resistance to conventional DNA-targeted anticancer drugs.Los complejos ciclometalados de platino luminiscentes son especies de interés debido principalmente a sus aplicaciones en los campos optoelectrónico y biológico, especialmente en lo que se refiere a su actividad anticancerígena. Dado este nivel de interés, se sintetizaron una serie de complejos ciclometalados (2-[2′-tienil]piridinato, thpy y 2-[2,4-difluorofenil]piridinato, dfppy) de platino con N-donante, PTA (1,3,5-triaza-7-fosfaadamantano) o ligandos derivados de crisina (incorporando fragmentos de piperidina, HL1, o morfolina, HL2). Los complejos son luminiscentes con longitudes de onda de emisión sintonizables. Se observó agregación en solución para [Pt(dfppy)L1], 5. Los estudios de teoría del funcional de la densidad (DFT) proporcionaron descripciones de las características del orbital molecular de mayor ocupación (HOMO) y del orbital molecular de menor desocupación (LUMO) y su influencia en las propiedades fotofísicas. Los orbitales de 5-6 eran de naturaleza diferente a los de 1-4. Los cálculos DFT dependientes del tiempo (TD-DFT) mostraron que para 1-4 los estados excitados S1 y T1 reflejan la transferencia de carga metal-ligando (MLCT) y contribuciones centradas en el ligando (LC) (C^N) mientras que para 5-6 estos estados son una transición LC centrada en L1 o L2. Se evaluó la especiación en DMSO y DMSO/H2O. Los estudios biológicos mostraron que [Pt(thpy)Cl(Hthpy)], 1, [Pt(dfppy)Cl(Hdfppy)], 2 y 5 ejercen una actividad citotóxica significativa frente a células humanas de carcinoma cervical (HeLa) y pulmonar (A549). La citotoxicidad de 1 se multiplicó por 2,84 tras la irradiación (azul). Los ensayos de microscopía con 5 mostraron que este compuesto se acumula en orgánulos citoplasmáticos, preferentemente en mitocondrias. El metabolismo mitocondrial se vio alterado por la actividad de los complejos, lo que provocó una disminución del contenido celular de adenosín trifosfato (ATP). En conjunto, los resultados muestran una actividad anticancerígena alternativa para los complejos 1, 2 y 5, que podría ser de gran interés para el tratamiento de tumores con resistencia adquirida a los fármacos anticancerígenos convencionales dirigidos al ADN

Effect of the aniline fragment in Pt(II) and Pt(IV) complexes as anti-proliferative agents. Standard reduction potential as a more reliable parameter for Pt(IV) compounds than peak reduction potential

The problems of resistance and side effects associated with cisplatin and other chemotherapeutic drugs have boosted research aimed at finding new compounds with improved properties. The use of platinum(IV) prodrugs is one alternative, although there is some controversy regarding the predictive ability of the peak reduction potentials. In the work described here a series of fourteen chloride Pt(II) and Pt(IV) compounds was synthesised and fully characterised. The compounds contain different bidentate arylazole heterocyclic ligands. Their cytotoxic properties against human lung carcinoma (A549), human breast carcinoma (MCF7) and human colon carcinoma (HCT116 and HT29) cell lines were studied. A clear relationship between the type of ligand and the anti-proliferative properties was found, with the best results obtained for the Pt(II) compound that contains an aniline fragment, (13), thus evidencing a positive effect of the NH2 group. Stability and aquation studies in DMSO, DMF and DMSO/water mixtures were carried out on the active complexes and an in-depth analysis of the two aquation processes, including DFT analysis, of 13 was undertaken. It was verified that DNA was the target and that cell death occurred by apoptosis in the case of 13. Furthermore, the cytotoxic derivatives did not exhibit haemolytic activity. The reduction of the Pt(IV) compounds whose Pt(II) congeners were active was studied by several techniques. It was concluded that the peak reduction potential was not useful to predict the ability for reduction. However, a correlation between the cytotoxic activity and the standard reduction potential was found.This work has been funded by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-100709-B-C21 to BRM, RTI2018-100709-B-C22 to AM, RTI2018-094093-B-I00 to RSP), Junta de Comunidades de Castilla-La Mancha-FEDER (JCCM) (grant SBPLY/19/180501/000260 to BRM), Ministerio de Economía y Competitividad (Project PID2019-104381GB-I00 to GC), Fundación Leticia Castillejo Castillo to MJRH, Junta de Castilla y León, Consejería de Educación y Cultura y Fondo Social Europeo (Projects BU263P18 and BU087G19 to JVC) as well as UCLM-FEDER (grants 2019-GRIN-27183 and 2019-GRIN-27209 to BRM) and University of Girona (MPCUdG2016/076 to AM)

Role of Seroalbumin in the Cytotoxicity of cis-Dichloro Pt(II) Complexes with (N^N)-Donor Ligands Bearing Functionalized Tails

Given the potent anticancer properties of cisdiamminedichloroplatinum( II) and knowing its mode of action, we synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4′-disubstituted bpy ligands (bpy = 2,2′-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By 1H NMR and UV−vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-“PtCl2” derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding.La Caixa Foundation (LCF/PR/PR12/11070003), Ministerio de Economía y Competitividad-FEDER (CTQ2014-58812-C2-2- R, CTQ2014-58812-C2-1-R, and CTQ2015-70371-REDT), Consejería de Educación−Junta de Castilla y León-FEDER (BU042U16), Spain

Base-free transfer hydrogenation of ketones using arene ruthenium(II) complexes

Ruthenium derivatives of the type [RuCl(arene)(NN)][BPh4] (arene = benzene, p-cymene) have been synthesized with NN = 2-hydroxyphenylbis(pyrazol-1-yl)methane (bpzmArOH) or 2-hydroxyphenylbis(3,5-dimethylpyrazol-1-yl)methane (bpz*mArOH). In the p-cymene derivative containing bpzmArOH, activation of the hydroxy group is observed and a scorpionate complex is obtained with the ligand behaving in a tridentate manner, [Ru(bpzmArO-κ3-N,N,O)(p-cymene)][BPh4]. The structure of this derivative and that of [RuCl(p-cymene)(bpz*mArOH)][BPh4] were determined by X-ray diffraction. The new derivatives, along with other compounds previously described by us that contain similar ligands, were tested in the transfer hydrogenation of benzophenone and other carbonyl compounds under base-free conditions without any other additive to promote the reaction. The precursors were active in this process, and the p-cymene derivatives exhibited a higher activity than the benzene complexes. For the p-cymene complexes the activity was even higher than that found in the presence of base (KOH). The effect of the substituents on the methylene carbon was also studied. Mechanistic and kinetic studies were carried out, and hydride species were observed after a pretreatment of the precatalyst in 2-propanol. Taking into account all of the results, a proposal for the mechanism taking place during the hydrogenation of carbonyl groups under base-free conditions has been made.Financial support from the Junta de Comunidades de Castilla-La Mancha-FEDER Funds (PCI-08-0054) and the Ministerio de Ciencia e Innovación, MICINN, for a project (CTQ2008-0378) and a Juan de la Cierva contract is acknowledged.Peer reviewe

Reactions of monocyclopentadienylniobium(III) complexes with α-diketones. Crystal structure of the phosphonium salt [P{C(OH)MeC(O)Me} Me2Ph]Cl

The reactions of Nb(η5-C5H5)Cl2(CO)L2 ( PMe3, PMe2Ph) with α-diketones RCOCOR (R Me, Ph) and 3,5-di-t-butyl-o-quinone have been studied. When L PMe2Ph and R Ph the reaction in a molar ratio 1 1 gives Nb(η5-C5H5)Cl2(O2C2Ph2)(PMe2Ph)2 (I) whereas the same reaction for R Me gives the phosphonium salt [P{C(OH)MeC(O)Me}Me2Ph]Cl (VII). When L PMe3 only the phosphonium salts [P{C(OH)RC(O)R}Me3]Cl are obtained for R Me (V) and Ph (VI), but the complex Nb(η5-C5H5)Cl2(O2C2Ph2)PMe3 (II) can be isolated by previous addition of MeI. Similar reactions with 3,5-di-t-butyl-o-quinone give Nb(η5-C5H5)Cl2(o-O2C6H2But)L, L PMe3 (III), PMe2Ph (IV). All the compounds have been characterized by IR, 1H, 13C, 31P NMR spectroscopy and the crystal structure of VII has been determined by X-ray diffraction. VII crystallizes in the monoclinic space group P21/c with a 7.440(2), b 10.377(3), c 17.644(4) Å, β 96.94(2)° and Dcal 1.039 g cm-3 for Z = 4. A final R value of 0.046 (Rw = 0.049) based on 2309 observed reflections was obtained. The geometry around the P atom is tetrahedral. © 1987.The authors gratefully acknowledge financial support from Comision Asesora de Investigation Cientifica y Técnica. (2001-83) Spain