Mono- and Polynuclear Complexes of the Model Nucleobase 1-Methylcytosine. Synthesis and Characterization of cis-[(PMe2Ph)2Pt{(1-MeCy(−H)}]3(NO3)3 and cis-[(PPh3)2Pt{1-MeCy(−H)}(1-MeCy)]NO3

The hydroxo complex cis-[L2Pt(μ-OH)]2(NO3)2 (L = PMe2Ph), in various solvents, reacts with 1-methylcytosine (1-MeCy) to give as the final product the cyclic species cis-[L2Pt{1-MeCy(−H),N 3N 4}]3(NO3)3 (1) in high or quantitative yield. X-ray analysis of 1 evidences a trinuclear species with the NH2-deprotonated nucleobases bridging symmetrically the metal centers through the N3 and N4 donors. A multinuclear NMR study of the reaction in DMSO-d6 reveals the initial formation of the dinuclear species cis-[L2Pt{1-MeCy(−H),N 3N 4}]22+ (2), which quantitatively converts into 1 following a first-order kinetic law (at 50 °C, t1/2 = 5 h). In chlorinated solvents, the deprotonation of the nucleobase affords as the major product (60−70%) the linkage isomer of 1, cis-[L2Pt{1-MeCy(−H)}]33+ (3), in which three cytosinate ligands bridge unsymmetrically three cis-L2Pt2+ units. In solution, 3 slowly converts quantitatively into the thermodynamically more stable isomer 1. No polynuclear adducts were obtained with the hydroxo complex stabilized by PPh3. cis-[(PPh3)2Pt(μ-OH)]2(NO3)2 reacts with 1-MeCy, in DMSO or CH2Cl2, to give the mononuclear species cis-[(PPh3)2Pt{1-MeCy(−H)}(1-MeCy)](NO3) (4) containing one neutral and one NH2-deprotonated 1-MeCy molecule, coordinated to the same metal center at the N3 and N4 sites, respectively. X-ray analysis and NMR studies show an intramolecular H bond between the N4 amino group and the uncoordinated N3 atom of the two nucleobases

Role of the ancillary ligands on the stabilization of the imino-oxo tautomer of 1-methylcytosine in PtII complexes

The mixed nucleobases complexes cis-[L2Pt{1-MeTy(-H)}(1-MeCy,N3)]NO3 (L = PPh3, 1a; PMePh2, 1b), containing the N(3)-deprotonated 1-methylthymine (1-MeTy(-H)) and the neutral 1-methylcytosine (1-MeCy) have been prepared and characterised. The compounds were obtained by reacting the hydroxo complexes cis-[L2Pt(μ-OH)]2(NO3)2 with 1-methylthymine (1-MeTy), followed by the addition of 1 equivalent of 1-MeCy. In solution of DMSO, DMF or chlorinated solvents, 1a converts quantitatively into the isomer cis-[L2Pt{1-MeTy(-H)}(1-MeCy,N4)]NO3 (2a) containing the tautomeric form of the cytosine stabilized through the coordination at the N(4) atom, as shown by single-crystal X-ray analysis. The structural determination of 2a shows the presence in the unit cell of two crystallographic independent complexes having similar conformation, with a different orientation of the two nucleobases (head–head and head–tail) according to the presence of both isomers in solution. Complex 1b, having the less hindered PMePh2 ligands, in DMSO solution, contains the tautomeric forms of the cytosine in equilibrium and the migration of the metal from the N(3) to N(4) site occurs only to a minor extent

Irreversible Insertion of Benzonitrile into Platinum ( II ) - Nitrogen Bonds of Nucleobase Complexes. Synthesis and Structural Characterization of Stable Azametallacycle Compounds

Deprotonation of 1-methylcytosine (1-MeCy) and 9-methyladenine (9-MeAd) promoted by cis-[L2Pt(μ-OH)]2(NO3)2 (L = PPh3, PMePh2, 1/2dppe) in PhCN causes the irreversible insertion of a nitrile molecule into the Pt−N4 and Pt−N6 bonds of the cytosinate and adeninate ligands, respectively, to form the stable azametallacycle complexes cis-[L2PtNH═C(Ph){1-MeCy(−2H)}]NO3 (L = PPh3, 1; PMePh2, 2; 1/2dppe, 3) and cis-[L2PtNH═C(Ph){9-MeAd(−2H)}]NO3 (L = PPh3, 4; PMePh2, 5) containing the deprotonated form of the molecules (Z)-9-N-(1-methyl-2-oxo-2,3-dihydropyrimidin-4(1H)-ylidene)benzimidamide and (Z)-N-(9-methyl-1H-purin-6(9H)-ylidene)benzimidamide. Single-crystal X-ray analyses of 2 and 4 show the metal coordinated to the N3 cytosine site [Pt−N3 = 2.112(7) Å̊] and to the N1 site of adenine [Pt−N1 = 2.116(6) Å̊] and to the nitrogen atom of the inserted benzonitrile [Pt−N2 = 2.043(6) and 2.010(6) Å̊ in 2 and 4, respectively], with the exocyclic nucleobase amino nitrogen bound to the carbon atom of the CN group. Complex 2, in solution, undergoes a dynamic process related to a partially restricted rotation around Pt−P bonds, arising from a steric interaction of the oxygen atom of the cytosine with one ring of the phosphine ligands. The reaction of 4 with acetylacetone (Hacac) causes the quantitative protonation of the anionic ligand, affording the acetylacetonate complex cis-[(PPh3)2Pt(acac)]NO3 and the free benzimidamide NH═C(Ph){9-MeAd(−H)}. In the same experimental conditions, complex 3 reacts with Hacac only partially

Investigating Cell Entry of Cisplatin and Anticancer Platinum(IV) Prodrugs Using Fluorescence Microscopy

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Pt(IV) Pro-Drugs with an Axial HDAC Inhibitor Demonstrate Multimodal Mechanisms Involving DNA Damage and a Poptosis Independent of Cisplatin Resistance in A2780/A2780cis Cells

Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance

Estrogens-functionalized metal complexes: selective anticancer and antibacterial activity

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Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells Author links open overlay panel

Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance

Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma

The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are describe

Sustainable Adoption of Connected Vehicles in the Brazilian Landscape: Policies, Technical Specifications and Challenges

This review addresses the intervehicular communication in Connected Vehicles (CV) by emphasizing V2V (vehicle-to-vehicle) and V2I (vehicle-to-infrastructure) communications in terms of evolution, current standards, state-of-the-art studies, embedded devices, simulation, trends, challenges, and relevant legislation. This review is based on studies conducted from 2009 to 2019, government reports about the sustainable deployment of these technologies and their adoption in the Brazilian automotive market. Moreover, WAVE (Wireless Access in Vehicular Environment) and DSRC (Dedicated Short-range Communication) standards, the performance analysis of communication parameters and intervehicular available at the market are also described. The current status of ITS (Intelligent Transportation System) development in Brazil was reviewed, as well as the research institutes and governmental actions focused on introducing the concept of connected vehicles into the society. The Brazilian outlook for technological adoption concerning CVs was also discussed. Moreover, challenges related to technical aspects, safety and environmental issues, and the standardization for vehicle communication are also described. Finally, this review highlights the challenges and proposals from available technologies devoted to the roads and vehicular infrastructure communication, their evolution and upcoming trends

Unique Pt5 metallacycle: [PtIICl(pyrrolidinedithiocarbamate)]5

3 páginas, 2 figuras, 1 tabla, 1 gráfico.The neutral complex [PtCl(PyDT)]5 (PyDT = (CH2)4NCS2−) represents the first example of a Pt5 metallacycle. This unique architecture based on chiral S-bridged PtII monomers was prepared by thermal degradation of the reaction product of PtCl2 and a pyrrolidinedithioester.This work was supported by the Consorzio Interuniversitario per la Ricerca Chimica dei Metalli nei Sistemi Biologici (CIRCMSB) and the Spanish Ministerio de Ciencia e Inovación (Ramón y Cajal Program).Peer reviewe