Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine.

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C16-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C3-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C7 in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds.

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu3(AlaLeu)3(H2O)3(CO3)]·PF6·H2O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H2O2 produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu-amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu-dipeptide-phen complexes are good SOD mimics but poor ROS producers. The activity of Cu-dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.

Preparation and mechanistic studies of 2-substituted Bisthiazolidines by imine exchange.

Bisthiazolidines (BTZ) are bicyclic compounds considered penicillin analogs that inhibit the full range of Metallo-ß-Lactamases (MBLs) and potentiate ß-lactam activity against resistant bacteria. Herein we present a new methodology to prepare 2-substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranged from 31 to 75%. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments and a key imine 1b-II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b-III by i) a N-assisted N-C bond cleavage, and ii) a thiol-mediated 5 endo-trig cyclization followed by a C-N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b-III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b-V.

Synthesis and Structure Insights of Two Novel Broad-Spectrum Antibacterial Candidates Based on (E)-N'-[(Heteroaryl)methylene]adamantane-1-carbohydrazides.

Two new N'-heteroarylidene-1-carbohydrazide derivatives, namely; E-N'-[(pyridine-3-yl)methylidene]adamantane-1-carbohydrazide (1) and E-N'-[(5-nitrothiophen-2-yl)methylidene]adamantane-1-carbohydrazide (2), were produced via condensation of adamantane-1-carbohydrazide with the appropriate heterocyclic aldehyde. Both compounds were chemically and structurally characterized by 1H-NMR, 13C-NMR, infrared and UV-vis spectroscopies, and single crystal X-ray diffraction. The study was complemented with density functional theory calculations (DFT). The results show an asymmetrical charge distribution in both compounds, with the electron density accumulated around the nitrogen and oxygen atoms, leaving the positive charge surrounding the N-H and C-H bonds in the hydrazine group. Consequently, the molecules stack in an antiparallel fashion in the crystalline state, although the contribution of the polar contacts to the stability of the lattice is different for 1 (18%) and 2 (42%). This difference affects the density and symmetry of their crystal structures. Both molecules show intense UV-Vis light absorption in the range 200-350 nm (1) and 200-500 nm (2), brought about by π → π* electronic transitions. The electron density difference maps (EDDM) revealed that during light absorption, the electron density flows within the π-delocalized system, among the pyridyl/thiophene ring, the nitro group, and the N'-methyleneacetohydrazide moiety. Interestingly, compounds 1 and 2 constitute broad-spectrum antibacterial candidates, displaying potent antibacterial activity with minimal inhibitory concentration (MIC) values around 0.5-2.0 µg/mL. They also show weak or moderate antifungal activity against the yeast-like pathogenic fungus Candida albicans.

Toluene Dioxygenase-Catalysed Oxidation of Benzyl Azide to Benzonitrile: Mechanistic Insights for an Unprecedented Enzymatic Transformation.

Enzymatic dioxygenation of benzyl azide by toluene dioxygenase (TDO) produces significant amounts of the cis-cyclohexadienediol derived from benzonitrile, along with the expected azido diols. We demonstrate that TDO catalyses the oxidation of benzyl azide to benzonitrile, which is further dioxygenated to produce the observed cis-diol. A proposed mechanism for this transformation involves initial benzylic monooxygenation followed by a nitrene-mediated rearrangement to form an oxime, which is further dehydrated to afford the nitrile. To the best of our knowledge, this is the first report of enzymatic oxidation of an alkyl azide to a nitrile. In addition, the described oxime-dehydration activity has not been reported for Rieske dioxygenases.

Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions.

Interaction of myo-inositol hexakisphosphate with biogenic and synthetic polyamines.

Within all the eukaryotic cells myo-inositol phosphates (InsPs) are an important group of biomolecules that are potentially related to signaling functions. The most abundant member of this family in nature is InsP6 (phytate, L(12-) in its fully deprotonated form). The complicated chemical behavior of this molecule demands a great effort to understand its function in the cell medium. In this work we follow our earlier studies on the interaction of InsP6 with metal cations by inclusion of polyamines (both biogenic and synthetic) as potential agents to produce stable adducts. The stability constants of InsP6-amine adducts and the relevant thermodynamic parameters ΔG°, ΔH°, and ΔS° were determined at 37.0 °C and 0.15 M ionic strength by means of potentiometric titrations and isothermal titration calorimetry (ITC). The biogenic amines studied were 1,4-diaminobutane (putrescine, put), 1,5-diaminopentane (cadaverine, cad), N-(3-aminopropyl)-1,4-diaminobutane (spermidine, spd), N,N'-bis(3-aminopropyl)-1,4-diaminobutane (spermine, spm), and 1-(4-aminobutyl)guanidine (agmatine, agm), while the synthetic models of longer polyamines were 1,19-dimethyl-1,4,7,10,13,16,19-heptaazanonadecane (Me2hexaen), 1,22-dimethyl-1,4,7,10,13,16,19,22-octaazadocosane (Me2heptaen), 1,25-dimethyl-1,4,7,10,13,16,19,22,25-nonaazapentacosane (Me2octaen) and N,N'-bis(3-aminopropyl)-1,3-propanediamine (3,3,3-tet). With the aid of molecular modeling, we also studied the structural aspects of molecular recognition in operation. The final result is a balance between many parameters including charge of the species, flexibility of the amines, H-bonds in the adduct, and desolvation processes.

One Scaffold, Two Conformations: The Ring-Flip of the Messenger InsP8 Occurs under Cytosolic Conditions.

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are central eukaryotic messengers. These very highly phosphorylated molecules can exist in two distinct conformations, a canonical one with five phosphoryl groups in equatorial positions, and a "flipped" conformation with five axial substituents. Using 13C-labeled InsPs/PP-InsPs, the behavior of these molecules was investigated by 2D-NMR under solution conditions reminiscent of a cytosolic environment. Remarkably, the most highly phosphorylated messenger 1,5(PP)2-InsP4 (also termed InsP8) readily adopts both conformations at physiological conditions. Environmental factors-such as pH, metal cation composition, and temperature-strongly influence the conformational equilibrium. Thermodynamic data revealed that the transition of InsP8 from the equatorial to the axial conformation is, in fact, an exothermic process. The speciation of InsPs and PP-InsPs also affects their interaction with protein binding partners; addition of Mg2+ decreased the binding constant Kd of InsP8 to an SPX protein domain. The results illustrate that PP-InsP speciation reacts very sensitively to solution conditions, suggesting it might act as an environment-responsive molecular switch.

Novel Adamantane-Linked Isothiourea Derivatives as Potential Chemotherapeutic Agents: Synthesis, Structural Insights, and Antimicrobial/Anti-Proliferative Profiles.

In this study, two adamantane-linked isothiourea derivatives containing a common 4-chlorophenyl substituent coupled with 4-nitrobenzyl or 4-bromobenzyl moieties were synthesized. Both derivatives were characterized, in the solid state and in solution, through a synergistic combination of experimental and in silico techniques, and the results are of great value for the chemical and structural characterization of related compounds. The crystal structures of both derivatives were analyzed in depth, including Hirshfeld surface analysis and lattice energy calculations, revealing a predominant dispersive component of the total energy that stabilizes crystal packing. Both compounds showed potent broad-spectrum antibacterial activity and moderate activity against the pathogenic fungus Candida albicans. In addition, in vitro anti-proliferative activity assays showed that the 4-bromobenzyl analogue displays higher activity than the 4-nitrobenzyl one, with IC50 values under 30 µM against five human cancer cell lines. Our results give evidence of the potential of the adamantane/isothiourea combination to render auspicious scaffolds for new potential chemotherapeutic agents.

Multifunctional organometallic compounds for the treatment of Chagas disease: Re(I) tricarbonyl compounds with two different bioactive ligands.

Chagas' disease (American Trypanosomiasis) is an ancient and endemic illness in Latin America caused by the protozoan parasite Trypanosoma cruzi. Although there is an urgent need for more efficient and less toxic chemotherapeutics, no new drugs to treat this disease have entered the clinic in the last decades. Searching for metal-based prospective antichagasic drugs, in this work, multifunctional Re(I) tricarbonyl compounds bearing two different bioactive ligands were designed: a polypyridyl NN derivative of 1,10-phenanthroline and a monodentate azole (Clotrimazole CTZ or Ketoconazol KTZ). Five fac-[Re(CO)3(NN)(CTZ)](PF6) compounds and a fac-[Re(CO)3(NN)(KTZ)](PF6) were synthesized and fully characterized. They showed activity against epimastigotes (IC50 3.48-9.42 µM) and trypomastigotes of T. cruzi (IC50 0.61-2.79 µM) and moderate to good selectivity towards the parasite compared to the VERO mammalian cell model. In order to unravel the mechanism of action of our compounds, two potential targets were experimentally and theoretically studied, namely DNA and one of the enzymes involved in the parasite ergosterol biosynthetic pathway, CYP51 (lanosterol 14-α-demethylase). As hypothesized, the multifunctional compounds shared in vitro a similar mode of action as that disclosed for the single bioactive moieties included in the new chemical entities. Additionally, two relevant physicochemical properties of biological interest in prospective drug development, namely lipophilicity and stability in solution in different media, were determined. The whole set of results demonstrates the potentiality of these Re(I) tricarbonyls as promising candidates for further antitrypanosomal drug development.

Fe(III)-Complex-Imprinted Polymers for the Green Oxidative Degradation of the Methyl Orange Dye Pollutant.

One of the biggest problems worldwide is the pollution of natural water bodies by dyes coming from effluents used in the textile industry. In the quest for novel effluent treatment alternatives, the aim of this work was to immobilize Fe(III) complexes in molecularly imprinted polymers (MIPs) to produce efficient Fenton-like heterogeneous catalysts for the green oxidative degradation of the methyl orange (MO) dye pollutant. Different metal complexes bearing commercial and low-cost ligands were assayed and their catalytic activity levels towards the discoloration of MO by H2O2 were assessed. The best candidates were Fe(III)-BMPA (BMPA = di-(2-picolyl)amine) and Fe(III)-NTP (NTP = 3,3',3″-nitrilotripropionic acid), displaying above 70% MO degradation in 3 h. Fe(III)-BMPA caused the oxidative degradation through two first-order stages, related to the formation of BMPA-Fe-OOH and the generation of reactive oxygen species. Only the first of these stages was detected for Fe(III)-NTP. Both complexes were then employed to imprint catalytic cavities into MIPs. The polymers showed catalytic profiles that were highly dependent on the crosslinking agent employed, with N,N-methylenebisacrylamide (MBAA) being the crosslinker that rendered polymers with optimal oxidative performance (>95% conversion). The obtained ion-imprinted polymers constitute cheap and robust solid matrices, with the potential to be coupled to dye-containing effluent treatment systems with synchronous H2O2 injection.

"Chelatable iron pool": inositol 1,2,3-trisphosphate fulfils the conditions required to be a safe cellular iron ligand.

Mammalian cells contain a pool of iron that is not strongly bound to proteins, which can be detected with fluorescent chelating probes. The cellular ligands of this biologically important "chelatable", "labile" or "transit" iron are not known. Proposed ligands are problematic, because they are saturated by magnesium under cellular conditions and/or because they are not "safe", i.e. they allow iron to catalyse hydroxyl radical formation. Among small cellular molecules, certain inositol phosphates (InsPs) excel at complexing Fe(3+) in such a "safe" manner in vitro. However, we previously calculated that the most abundant InsP, inositol hexakisphosphate, cannot interact with Fe(3+) in the presence of cellular concentrations of Mg(2+). In this work, we study the metal complexation behaviour of inositol 1,2,3-trisphosphate [Ins(1,2,3)P(3)], a cellular constituent of unknown function and the simplest InsP to display high-affinity, "safe", iron complexation. We report thermodynamic constants for the interaction of Ins(1,2,3)P(3) with Na(+), K(+), Mg(2+), Ca(2+), Cu(2+), Fe(2+) and Fe(3+). Our calculations indicate that Ins(1,2,3)P(3) can be expected to complex all available Fe(3+) in a quantitative, 1:1 reaction, both in cytosol/nucleus and in acidic compartments, in which an important labile iron subpool is thought to exist. In addition, we calculate that the fluorescent iron probe calcein would strip Fe(3+) from Ins(1,2,3)P(3) under cellular conditions, and hence labile iron detected using this probe may include iron bound to Ins(1,2,3)P(3). Therefore Ins(1,2,3)P(3) is the first viable proposal for a transit iron ligand.

The behaviour of inositol 1,3,4,5,6-pentakisphosphate in the presence of the major biological metal cations.

The inositol phosphates are ubiquitous metabolites in eukaryotes, of which the most abundant are inositol hexakisphosphate (InsP 6) and inositol 1,3,4,5,6-pentakisphosphate [Ins(1,3,4,5,6)P5)]. These two compounds, poorly understood functionally, have complicated complexation and solid formation behaviours with multivalent cations. For InsP 6, we have previously described this chemistry and its biological implications (Veiga et al. in J Inorg Biochem 100:1800, 2006; Torres et al. in J Inorg Biochem 99:828, 2005). We now cover similar ground for Ins(1,3,4,5,6)P5, describing its interactions in solution with Na+, K+, Mg2+, Ca2+, Cu2+, Fe2+ and Fe3+, and its solid-formation equilibria with Ca2+ and Mg2+. Ins(1,3,4,5,6)P5 forms soluble complexes of 1:1 stoichiometry with all multivalent cations studied. The affinity for Fe3+ is similar to that of InsP6 and inositol 1,2,3-trisphosphate, indicating that the 1,2,3-trisphosphate motif, which Ins(1,3,4,5,6)P5 lacks, is not absolutely necessary for high-affinity Fe3+ complexation by inositol phosphates, even if it is necessary for their prevention of the Fenton reaction. With excess Ca2+ and Mg2+, Ins(1,3,4,5,6)P5 also forms the polymetallic complexes [M4(H2L)] [where L is fully deprotonated Ins(1,3,4,5,6)P5]. However, unlike InsP6, Ins(1,3,4,5,6)P5 is predicted not to be fully associated with Mg2+ under simulated cytosolic/nuclear conditions. The neutral Mg2+ and Ca2+ complexes have significant windows of solubility, but they precipitate as [Mg4(H2L)] x 23H2O or [Ca4(H2L)] x 16H2O whenever they exceed 135 and 56 microM in concentration, respectively. Nonetheless, the low stability of the [M4(H2L)] complexes means that the 1:1 species contribute to the overall solubility of Ins(1,3,4,5,6)P 5 even under significant Mg2+ or Ca2+ excesses. We summarize the solubility behaviour of Ins(1,3,4,5,6)P5 in straightforward plots.

Solution Studies and Crystal Structures of Heteropolynuclear Potassium/Copper Complexes with Phytate and Aromatic Polyamines: Self-Assembly through Coordinative and Supramolecular Interactions.

Phytate (L12- ) is a relevant natural product. It interacts strongly with biologically relevant cations, due to the high negative charge exhibited in a wide pH range. The synthesis and crystal structures of the mixed-ligand Cu(II) polynuclear complexes K(H2 tptz)0.5 [Cu(H8 L)(tptz)] ⋅ 3.6H2 O (1), K(H2 O)3 {[Cu(H2 O)(bpca)]3 (H8 L)} ⋅ 1.75H2 O (2), and K1.5 (H2 O)2 [Cu(bpca)](H9.5 L) ⋅ 8H2 O (3) (tptz=2,4,6-tri(pyridin-2-yl)-1,3,5-triazine; Hbpca=bis(2-pyridylcarbonyl) amine) are reported herein. They were obtained by the use of an aromatic rigid amine, which satisfies some of the metal coordination sites and promotes the hierarchical assembly of 2D polymeric structures. Speciation of phytate-Cu(II)-Hbpca system and determination of complex stability constants were performed by means of potentiometric titrations, in 0.15 M NMe4 Cl at 37.0 °C, showing that, even in solution, this system is able to produce highly aggregated complexes, such as [Cu3 (bpca)3 (H7 L)]2- . Furthermore, the Cu(II)-mediated tptz hydrolysis was studied by UV-vis spectroscopy at room temperature in 0.15 M NMe4 Cl. Based on the equilibrium results and with the aid of molecular modelling tools, a plausible self-assembly process for 2 and 3 could be proposed.

Self-Assembly of Manganese(II)-Phytate Coordination Polymers: Synthesis, Crystal Structure, and Physicochemical Properties.

myo-Inositol phosphates are an important group of biomolecules that are present in all eukaryotic cells. The most abundant member of this family in nature is InsP6 (phytate, L12- in its fully deprotonated form). Phytate interacts strongly with inorganic and organic cations, and this interaction is essential for determining the possible functions of this biomolecule. Herein, the chemical, thermodynamic, and structural characterization of phytate-MnII species is presented in a study aimed at understanding how the interaction of the two components modulates their biological roles and their bioavailability. Polynuclear complexes Mn5 (H2 L)⋅16 H2 O (1) and (H2 terpy)2 [Mn(H6 L)(terpy)(H2 O)]⋅17 H2 O (terpy=terpyridine) (2) were prepared and characterized by different techniques. The isolation of 1 and the determination of its solubility, together with potentiometric titrations of the MnII -phytate system, allow the full description of this binary system. The preparation and crystal structure of 2 show a novel coordination mode of phytate, that is, the formation of infinite polymeric chains through equatorial phosphate groups.

Characterization of myo-inositol hexakisphosphate deposits from larval Echinococcus granulosus.

The abundant metabolite myo-inositol hexakisphosphate (InsP6) can form vesicular deposits with cations, a widespread phenomenon in plants also found in the cestode parasite, Echinococcus granulosus. In this organism, the deposits are exocytosed, accumulating in a host-exposed sheath of extracellular matrix termed the laminated layer. The formation and mobilization of InsP6 deposits, which involve precipitation and solubilization reactions, respectively, cannot yet be rationalized in quantitative chemical terms, as the solids involved have not been formally described. We report such a description for the InsP6 deposits from E. granulosus, purified as the solid residue left by mild alkaline digestion of the principal mucin component of the laminated layer. The deposits are largely composed of the compound Ca5H2L.16H2O (L representing fully deprotonated InsP6), and additionally contain Mg2+ (6-9% molar ratio with respect to Ca2+), but not K+. Calculations employing recently available chemical constants show that the precipitation of Ca5H2L.16H2O is predicted by thermodynamics in secretory vesicle-like conditions. The deposits appear to be similar to microcrystalline solids when analysed under the electron microscope; we estimate that each crystal comprises around 200 InsP6 molecules. We calculate that the deposits increase, by three orders of magnitude, the surface area available for adsorption of host proteins, a salient ability of the laminated layer. The major inositol phosphate in the deposits, other than InsP6, is myo-inositol (1,2,4,5,6) pentakisphosphate, or its enantiomer, inositol (2,3,4,5,6) pentakisphosphate. The compound appears to be a subproduct of the intracellular pathways leading to the synthesis and vesicular accumulation of InsP6, rather than arising from extracellular hydrolysis of InsP6.

The behaviour of myo-inositol hexakisphosphate in the presence of magnesium(II) and calcium(II): protein-free soluble InsP6 is limited to 49 microM under cytosolic/nuclear conditions.

Progress in the biology of myo-inositol hexakisphosphate (InsP(6)) has been delayed by the lack of a quantitative description of its multiple interactions with divalent cations. Our recent initial description of these [J. Torres, S. Dominguez, M.F. Cerda, G. Obal, A. Mederos, R.F. Irvine, A. Diaz, C. Kremer, J. Inorg. Biochem. 99 (2005) 828-840] predicted that under cytosolic/nuclear conditions, protein-free soluble InsP(6) occurs as Mg(5)(H(2)L), a neutral complex that exists thanks to a significant, but undefined, window of solubility displayed by solid Mg(5)(H(2)L).22H(2)O (L is fully deprotonated InsP(6)). Here we complete the description of the InsP(6)-Mg(2+)-Ca(2+) system, defining the solubilities of the Mg(2+) and Ca(2+) (Ca(5)(H(2)L).16H(2)O) solids in terms of K(s0)=[M(2+)](5)[H(2)L(10-)], with pK(s0)=32.93 for M=Mg and pK(s0)=39.3 for M=Ca. The concentration of soluble Mg(5)(H(2)L) at 37 degrees C and I=0.15M NaClO(4) is limited to 49muM, yet InsP(6) in mammalian cells may reach 100muM. Any cytosolic/nuclear InsP(6) in excess of 49muM must be protein- or membrane-bound, or as solid Mg(5)(H(2)L).22H(2)O, and any extracellular InsP(6) (e.g. in plasma) is surely protein-bound.

Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer.

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC50 for both Cu-Ala-Phe (IC50=4.5) and Cu-Phe-Ala (IC50=45). The computational results permitted to explain this behavior proposing that it is feasible that the O2- anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin.

Double [3,3]-sigmatropic rearrangement in the enzymatic dioxygenation of benzyl azide: preparation of novel synthetically valuable azido-diols.

Enzymatic dioxygenation of benzyl azide by toluene dioxygenase produces the expected enantiopure cis-cyclohexadienediol along with an exocyclic diene formed by a spontaneous sequence of two [3,3] sigmatropic shifts. This novel dienediol presents high synthetic potential for natural product synthesis. The sigmatropic rearrangements can be reversed by protection of the diol moiety. An optimized production protocol for either of these valuable diols is presented.

The copper(II)-phytate-terpyridine ternary system: the first crystal structures showing the interaction of phytate with bivalent metal and ammonium cations.

Phytate, an abundant molecule in eukaryotic cells, interacts strongly with inorganic cations and polyamines. This interaction is essential for determining the possible functions of this biomolecule. We present here the first solution and crystallographic study of the formation of phytate complexes in the Cu(II)-phytate-terpy and phytate-terpy (terpy = 2,2':6',2''-terpyridine) systems.