Synthesis, reactivity studies, and cytotoxicity of two trans-Iodidoplatinum(II) complexes. Does photoactivation work?

trans-Platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes signaled a new turning point in the platinum drug design field when their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodidoplatinum complexes trans-[PtI2(amine)(pyridine)] bearing aliphatic amines (isopropylamine and methylamine) and pyridines in trans configuration. X-ray diffraction data support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D, and HCT116. Moreover, we report their solution behavior and reactivity with biological models. Ultraviolet-a (UVA) irradiation induces an increase in their reactivity towards model nucleobase 5′-GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.MINECO CTQ-2015-68779

Mitosene-DNA adducts. Characterization of two major DNA monoadducts formed by 1,10-bis(acetoxy)-7-methoxymitosene upon reductive activation

Reductive activation of racemic 1,10-bis(acetoxy)-7-methoxymitosene WV15 in the presence of DNA, followed by enzymatic digestion and HPLC analysis, revealed the formation of various DNA adducts. Reduction is a necessary event for adduct formation to occur. This reductive activation was performed under hypoxic conditions in various ways:  (1) chemically, using a 2-fold excess of sodium dithionite (Na2S2O4), (2) enzymatically using NADH-cytochrome c reductase, (3) electrochemically on a mercury pool working electrode, and (4) catalytically, using a H2/PtO2 system. Five different mitosene−DNA adducts were detected. These adducts were also present when poly(dG-dC) was used instead of DNA, but were absent with poly(dA-dT). All were shown to be adducts of guanine. Reduction of 1,10-dihydroxymitosene WV14 in the presence of DNA did not result in detectable adduct formation, demonstrating the importance of good leaving groups for efficient adduct formation by these mitosenes. Finally, two of the adducts were isolated and their structures elucidated, using mass spectrometry, 1H NMR and circular dichroism (CD). The structures were assigned as the diastereoisomers N2-(1‘ ‘-n-hydroxymitosen-10‘ ‘-yl), 2‘-deoxyguanosine (n = α or β). These type of adducts, in which the mitosene C-10 is covalently bonded to the N-2 of a guanosylic group, are different from the well-known mitomycin C 2‘-deoxyguanosine monoadducts, that is linked via the mitomycin C C-1 position, demonstrating that the order of reactivity of the C-1 and C-10 in these mitosenes is reversed, as compared to mitomycin C. The 7-methoxy substituent of WV15 is a likely factor causing this switch. Evidence is presented that the 7-substituent of mitosenes also influences their DNA alkylation site. Adducts 4 and 5 represent the first isolated and structurally characterized covalent adducts of DNA and a synthetic mitosene

Reaction of cis- and trans-Dichlorotetra(Dimethylsulfoxide)Ruthenium(II) With the Antiviral Drug Acyclovir

NMR was used to investigate the reaction of cis- and trans-[RuCl2(DMSO)4] with the antiviral drug acyclovir, a guanine derivative containing the acyclic (2-hydroxo) ethoxymethyl pendant linked to N(9). Studies were performed in aqueous solutions at ambient temperature and at 37 °C, and at various molar ratios. Both isomers yielded two compounds, a monoadduct and a bisadduct, the relative yields being dependent upon the metal to ligand concentration ratios. The products derived from the two Ru isomers displayed identical NMR spectra, suggesting that they have the same coordination environment, however the rate of formation of the monoadduct was higher in the case of the trans isomer than in the case of the cis isomer, while the rate of conversion of the monoadduct into the bisadduct appeared to be similar in both cases. As a consequence in the case of the trans isomer there is accumulation of monoadduct in the early stage of the reaction, whose concentration afterwards decreases with the progress of the reaction. As for platinum, also for ruthenium the preferred binding site is N(7) of the purine base, however, in the case of ruthenium a discrete amount of bisadduct is formed even in the presence of an excess of metallic substrate with respect to the acyclovir ligand; under similar conditions a platinum substrate would have given, nearly exclusively, the monoadduct

Solid state physicochemical properties and applications of organic and metallo-organic fullerene derivatives

We review the fundamental properties and main applications of organic derivatives and complexes of fullerenes in the solid-state form. We address in particular the structural properties, in terms of crystal structure, polymorphism, orientational transitions and morphology, and the electronic structure and derived properties, such as chemical activity, electrical conduction mechanisms, optical properties, heat conduction and magnetism. The last two sections of the review focus on the solid-state optoelectronic and electrochemical applications of fullerene derivatives, which range from photovoltaic cells to field-effect transistors and photodetectors on one hand, to electron-beam resists, electrolytes and energy storage on the other.Peer ReviewedPreprin

Synthesis of 6-thiosubstituted pentacenes and study of an unexpected photorearrangement of 6-phenylthiopentacene dimer

Two new monosubstituted pentacene derivatives, 6-phenylthiopentacene, 26, and 6-acetylthiopentacene, 27, have been prepared using a dehydrogenative aromatization and elimination reaction that utilizes 1,8-diazabicycloundec-7-ene (DBU) as reagent. Although many disubstituted pentacenes have been synthesized and characterized, monosubstituted pentacenes have received much less attention. While studying the photodegradation of 26 under ambient light and air conditions, an unexpected transformation to 6,13-bis(phenylthio)pentacene, 32, was observed. The transformation requires short wavelength (254 nm) UV irradiation. Through a combined experimental and computational study, we have identified this transformation as a multi-step intramolecular process initiated by the photoexcitation of the endo anti dimer of 26. The photoexcited dimer undergoes an intramolecular acid-base reaction which involves two proton transfers and nucleophilic substitution to form the rearranged photodimer which upon dissociation yields bisadduct 32. Using 254 nm light and a quartz reaction vessel, bisadduct 32 has been isolated in 20% yield from monoadduct 26

Kinetic and Thermodynamic Studies of Copper-Catalyzed Atom Transfer Radical Processes in the Presence of Free-Radical Diazo Initiators as Reducing Agents

The first part of this dissertation focuses on the kinetic aspects of atom transfer radical addition (ATRA) in the presence of reducing agents. The rate of alkene consumption was found to be dependent on the initial concentration of the radical initiator and its decomposition and termination rate constants but not on the concentrations of CuI and CuII, which was contrary to the rate law for copper-catalyzed ATRA in the absence of a reducing agent. Kinetic experiments showed that the observed rate of ATRA (kobs) was indeed not dependent on the concentration of the catalyst, which supported the newly derived rate law. However, product selectivity was highly dependent on the nature of the catalyst. The activation (ka,AIBN) and deactivation (kd,AIBN) rate constants of various CuII/AIBN systems were determined through a combination of experimental and theoretical methods and were found to control the overall concentrations of CuI and CuII at equilibrium. The effect of the catalyst, alkyl halide, and free radical initiator concentrations on the percent conversion and yield of monoadduct were also investigated. Lower catalyst loadings in ATRA reactions involving reactive monomers led to a decrease in monoadduct yield due to competing polymerization reactions. Low-temperature ATRA reactions were found to significantly increase the formation of the monoadduct as a result of the lowering of the rate constant of propagation (kp). Reactions of less active halides were more affected by increased alkyl halide concentrations than that of the more active alkyl halides. Higher free radical initiator concentration led to an increase in AIBN-initiated polymer formation. The second part explores the role of thermodynamic factors on the product selectivity of atom transfer radical cyclization (ATRC). Various derivatives of alkenyl bromoacetate and trichloroacetate were synthesized and characterized by 1H NMR spectroscopy. Theoretical calculation of the relative energies of the s-trans and s-cis conformers revealed that the presence of bulky substituents on the carbon atom adjacent to the acetate moiety stabilizes the s-cis conformation and, thus, promotes cyclization. This was experimentally confirmed in the ATRC reactions of the synthesized alkenyl haloacetates in which the addition of bulky groups increased the yields of cyclic products