Expanding the Range of Pyrenylphosphines and Their Derived Ru(II)-Arene Complexes

Laia Rafols, Sara Torrente, David Aguilà, Vanessa Soto-Cerrato, Ricardo Pérez-Tomás, Patrick Gamez, and Arnald Grabulosa

Organometallics 2020, 39, 2959-2971.

The precursor PPyrCl2 (Pyr = 1-pyrenyl) has been used to prepare a number of novel 1-pyrenylphosphines. Treatment of PPyrCl2 with methylmagnesium chloride has provided the phosphine PPyrMe2, with methanol/triethylamine, the phosphonite PPyr(OMe)2 (1), with dimethylamine/triethylamine, the diaminophosphine PPyr(NMe2)2 (2), and with lithium aluminum hydride, PPyrH2 (3). From this primary phosphine, phosphirane PPyr(CH2CH2) (5) has been obtained. The phosphine PPyr2Ph (6) has been synthesized from 1-bromopyrene, while 1-bromo-2-(1-pyrenyl)benzene has been used to prepare Ph-PyrPhos (7) and i-Pr-PyrPhos (8). The new phosphines have subsequently been used to obtain the corresponding [RuCl2(η6-arene)(PPyrR2)] complexes C1Cym–C3Cym  and C6Cym–C8Cym (arene = p-cymene; Cym) and C1Mba–C3Mba  and C6Mba–C8Mba  (arene = methyl benzoate; Mba), which have been fully characterized; the crystal structures of C1Cym, C1Mba, C2Cym, C2Mba, C6Mba, and C7Cym  were determined by X-ray diffraction. Substitution of the methyl benzoate fragment of complexes C7Mba  and C8Mba  by the η6-coordinated pyrenyl group of the coordinated phosphine was achieved photochemically, giving the tethered complexes C7Tet  and C8Tet. In these two complexes the phosphine acts as a κ1,η6-coordinated ligand, as evidenced by the X-ray structure of C8Tet. The antineoplastic activities of the piano-stool Ru compounds revealed that they are highly phosphine dependent and two compounds, namely C1Cym  and C2Cym, exhibit interesting biological properties.

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Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6

F. Javier Pérez-Areales, María Garrido, Ester Aso, Manuela Bartolini, Angela De Simone, Alba Espargaro, Tiziana Ginex, Raimon Sabaté, Belén Pérez, Vincenza Andrisano, Dolors Puigoriol-Illamola, Mercè Pallàs, F. Javier Luque, María Isabel Loza, José M. Brea, Isidre Ferrer, Francisco Ciruela, Angel Messeguer, and Diego Muñoz-Torrero

J. Med. Chem. 2020, 63, 9360-9390.

Oxidative stress is a major pathogenic factor in Alzheimer’s disease, but it should not be tackled alone but together with other key targets to derive effective treatments. Combination of the scaffold of the polar antioxidant lead CR-6 (7-methoxy-2,2-dimethylchroman-6-ol) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, BACE-1, and Aβ42 and tau aggregation inhibition). In in vivo studies in wild-type and APP/PS1 mice, two selected compounds were well tolerated and led to positive trends, albeit statistically non-significant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes SOD2, catalase, GPX1, and Hmox1, and transcription factor Nrf2). These compounds emerge as interesting brain permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.

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Evaluation of cobalt(III) complexes as potential hypoxia-responsive carriers of esculetin

Marcos V. Palmeira-Mello, Ana B. Caballero, Juliana Martins Ribeiro, Elaine Maria de Souza-Fagundes, Patrick Gamez, Mauricio Lanznaster

J. Inorg. Biochem. 2020, 211, 111211.

Differentiation between hypoxic and normoxic tissues have been exploited for the development of selective chemotherapeutic agents. In this context, cobalt(III)-based coordination compounds have been designed and investigated as prospective hypoxia-responsive drug delivery systems. Three cobalt(III) complexes, namely

[CoIII(esc)(py2en)]ClO4·(CH3OH)2 (1) [CoIII(esc)(TPA)]ClO4·3H2O (2) and [CoIII(bipy)2(esc)]ClO4·2.5H2O (3) (py2en = N,N′-bis(pyridin-2-ylmethyl)ethylenediamine, TPA = tris(2-pyridylmethyl)amine and bipy = 2,2′-bipyridine, and esc = 6,7-dihydroxycoumarin or esculetin), were prepared and investigated as potential carriers of esculetin. The spectroscopic and electrochemical properties of 1–3 were investigated and compared. Reactions of the complexes with biologically relevant reduction agents, viz. ascorbic acid, cysteine and glutathione, were monitored spectroscopically for 24 h, in pH 6.2 and 7.4 PBS phosphate buffer saline (PBS) solutions at 37 °C, under air, argon and dioxygen atmospheres. Dissociation of esculetin was observed upon Co3+/Co2+ reduction preferably under hypoxic conditions, with more effective conversion rates for 3 > 2 > 1. These results illustrate the importance to modulate the Co3+/Co2+ redox potential through the donor-acceptor properties of the ancillary ligands. Complex 3  is cytotoxic against HCT-116 but not against HT-29 and HEK-293 cells. In addition, DNA-binding studies indicate that interactions between 1  and 3  and the biomolecule are electrostatic.

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Thiosemicarbazone Derivatives as Inhibitors of Amyloid-β Aggregation: Effect of Metal Coordination

Ana I. Matesanz, Ana B. Caballero, Carmen Lorenzo, Alba Espargaró, Raimon Sabaté, Adoración G. Quiroga, Patrick Gamez

Inorg. Chem. 2020, 59, 6978-6987.

Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL1), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL2), and 4-(dimethylamino)benzaldehyde 4-methylthiosemicarbazone (HL3), have been synthesized and characterized. The three palladium(II) complexes 1–3 were prepared respectively from HL1, HL2, and HL3. The crystal structures of two coordination compounds, namely Pd(L2)2 (2) and Pd(L3)2 (3), were obtained, which showed the expected square-planar environment for the metal centers. The ligand HL3 and the Pd(II) complexes 1–3, which are stable in buffered solutions containing up to 5% DMSO, exhibit remarkable inhibitory properties against the aggregation of amyloid-β, reducing the formation of fibrils. HL1, HL3, 2, and 3 display IC50 values (i.e., the concentrations required to reduce Aβ fibrillation by 50%) below 1 μM, lower that of the reference compound catechin (IC50 = 2.8 μM). Finally, in cellulo studies with E. coli cells revealed that the palladium(II) compounds are significantly more efficient than the free ligands in inhibiting Aβ aggregation inside bacterial inclusion bodies, thus illustrating a beneficial effect of metal coordination.

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Time‐Dependent Cytotoxic Properties of Terpyridine‐Based Copper Complexes

Jordi Grau, Amparo Caubet, Olivier Roubeau, David Montpeyó, Julia Lorenzo, Patrick Gamez

ChemBioChem 2020, 21, 2348-2355.

Five copper complexes supported by terpyridine ligands were prepared and characterized, viz. [Cu3Cl4(Naphtpy)2][CuCl2] (1), [Cu2Cl2(Naphtpy)2](ClO4)2 (2), [CuCl2(Naphtpy)]2(MeOH)3(H2O) (3), [CuCl2(Cltpy)] (4) and [Cu(Cltpy)2](ClO4)2 (5); (where Naphtpy stands for 4’-((naphthalen-2-yl)methoxy)-2,2′:6′,2′′-terpyridine and Cltpy for 4′-chloro-2,2′:6′,2′′-terpyridine). Their DNA-interaction abilities were investigated, and their cytotoxic behaviors were examined with three cells lines, namely with human ovarian carcinoma cells (A2780) and its derived cisplatin-resistant line (A2780cis), and human cervix adenocarcinoma cells (HeLa). All compounds show good cytotoxic properties (especially after 72 h incubation). Remarkably, two compounds, i.e. 4 and 5, are almost inactive after 24 h (particularly 4), but are highly active after 72 h, with IC50 values in the low micromolar to submicromolar range. Compounds 1 and 2 induce necrosis, whereas late apoptosis is observed with 3−5, 4  exhibiting a behaviour close to that of cisplatin.

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