Inequivalent Solvation Effects on the N 1s Levels of Self-Associated Melamine Molecules in Aqueous Solution.

This work shows how the N 1s photoemission (PE) spectrum of self-associated melamine molecules in aqueous solution has been successfully rationalized using an integrated computational approach encompassing classical metadynamics simulations and quantum calculations based on density functional theory (DFT). The first approach allowed us to describe interacting melamine molecules in explicit waters and to identify dimeric configurations based on π-π and/or H-bonding interactions. Then, N 1s binding energies (BEs) and PE spectra were computed at the DFT level for all structures both in the gas phase and in an implicit solvent. While pure π-stacked dimers show gas-phase PE spectra almost identical to that of the monomer, those of the H-bonded dimers are sensibly affected by NH···NH or NH···NC interactions. Interestingly, the solvation suppresses all of the non-equivalences due to the H-bonds yielding similar PE spectra for all dimers, matching very well our measurements.

Probing Intermolecular H-Bonding Interactions in Cyanuric Acid Networks: Quenching of the N K-Edge Sigma Resonances.

The electronic characterization of the cyanuric acid both in gas phase and when embedded within an H-bonded scheme forming a monolayer on the Au(111) surface has been performed by means of X-ray Photoelectron Spectroscopy (XPS) and Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy. The experimental spectra at the N, O, and C K-edges have been assigned with the support of DFT calculations, and the combination between theory and experiment has allowed to us investigate the effect of the H-bonding intermolecular interaction on the spectra. In particular, the H-bond formation in the monolayer leads to a quenching of the N 1s NEXAFS resonances associated with transitions to the sigma empty orbitals localized on the N-H portion of the imide group. On the other hand, the π* empty states remain substantially unperturbed. From a computational point of view, it has been shown that the DFT-TP scheme is not able to describe the N 1s NEXAFS spectra of these systems, and the configuration mixing has to be included, through the TDDFT approach in conjunction with the range-separated XC CAM-B3LYP functional, to obtain a correct reproduction of the N 1s core spectra.

Bis(CBT)palladium(II) Derivatives (CBT = m-carborane-1-thiolate): Synthesis, Molecular Structure, and Physicochemical Properties of cis-[(bipy)Pd(CBT)2] and trans-[(py)2Pd(CBT)2].

The new synthesized PdII complex cis-[(bipy)Pd(CBT)2] (bipy = 2,2'-bipyridyl; CBT = m-carborane-1-thiolate anion), which is a potential BNCT (boron neutron capture therapy) agent and of structure elucidated by single-crystal X-ray work, has been studied by infrared (IR) and ultraviolet-visible light (UV-vis) spectra and its properties compared with those of the previously reported and also the structurally characterized analogue trans-[(py)2Pd(CBT)2]. This trans species, prepared via a direct method, was previously isolated from a pyridine solution, consequent to the occurring releasing of the external Pd(CBT)2 moieties of the porphyrazine macrocycle [{Pd(CBT)2}4LZn]·xH2O (L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion), which is an active photosensitizer in photodynamic therapy (PDT) and a potential bimodal PDT/BNCT agent. The UV-vis spectral behavior of both cis and trans species in CHCl3 solution and in the gas phase has been examined in detail by density functional theory (DFT) and time-dependent density functional theory (TDDFT) studies devoted to explain their distinct behavior observed in the region of 400-500 nm, as determined by the presence in the cis structure of a vicinal arrangement of the two CBT groups, an ensemble of results closely similar to those observed for the macrocycles [{Pd(CBT)2}4LM]·xH2O (M = MgII(H2O), ZnII, PdII). It has also been experimentally proved the tendency of the cis isomer in CHCl3/pyridine solution to be changed to the respective trans analogue, with conversion occurring in two steps, as interpreted by detailed DFT studies.

Homo/Heteropentanuclear Porphyrazine MgII, ZnII, and PdII Macrocycles with Externally Pending PdCl2 and Pd(CBT)2 Units: Synthesis, Physicochemical Characterization, and Photoactivity Studies.

Recent work has been developed on two new classes of neutral porphyrazine complexes of formulas [(PdCl2)4Py8PzM]·xH2O (Py8Pz = octakis(2-pyridyl)porphyrazinato anion; M = MgII(H2O), ZnII, PdII) and [{Pd(CBT)2}4Py8PzM]·xH2O (M = MgII(H2O), ZnII; CBT = m-carborane-1-thiolate anion). Characterization of all the species has been conducted by IR and UV-visible spectral measurements in a systematic comparison with the corresponding already known mononuclear species [Py8PzM] (M = MgII(H2O), ZnII) and the mono-PdII analogue isolated and presented here for the first time. Comparison includes also the two parent classes of pentanuclear tetrapyrazinoporphyrazines having the more extended π-electron delocalized macrocyclic core Py8TPyzPz. The reported new classes of pentanuclear complexes behave as active photosensitizers in photodynamic therapy (PDT), and due to the high boron content of the CBT derivatives, perspectives for them are open of application in the field of bimodal PDT/BNCT (boron neutron capture therapy) anticancer treatments.

Palladium(II) and Platinum(II) Mononuclear Complexes and Tendency to Undergo Dehydrogenation of the Multiple N-Donor Ligand Di-(2-pyridyl)dihydropyrazine.

The already known di(2-pyridyl)dihydropyrazine (dhdpp) was prepared and isolated also in the form of a bis-hydrated species, i.e., dhdpp·2H2O. As established by X-ray work, a small amount of single crystals of di(2-pyridyl)-pyrazine (dpp) was also obtained from the mother liquors, this testifying the possibility of a dehydrogenation process dhdpp → dpp in the absence of a catalyst. Using dhdpp as a ligand, mononuclear metal derivatives of formula [(dhdpp)MCl2]·xH2O (M = PdII, PtII) were obtained as stable-to-air solids, studied by X-ray powder, IR, UV-visible, and 1H NMR spectra, and proved to exhibit a N2MCl2 coordination site involving one pyridine and one pyrazine N atom ("py-pyz" coordination). An interesting relationship has been established in terms of the observed types of coordination with the analogs of di(2-pyridyl)-pyrazine (dpp) formulated as [(dpp)MCl2]·3H2O, proved also by 1H NMR spectra to exhibit the "py-pyz" mode of coordination. Attempts to isolate from the reaction of dhdpp with Pd(OAc)2 the corresponding mononuclear derivatives were shown to lead, as definitely supported by 1H NMR spectral data and crystallographic work, to the exclusive formation of the corresponding dpp complex [(dpp)Pd(OAc)2]·5H2O ("py-pyz" coordination site), this proving the tendency of dhdpp to generate dpp under different reaction conditions. The promoted conversion of dhdpp into dpp in the complex was examined by sequential NMR analysis and established to be determined by Pd(OAc)2 which plays the role of catalyst. The new salt-like species [(CH3)(dhdpp)PdI2](I)·7H2O, prepared starting from [(dhdpp)PdCl2] in its reaction with CH3I, allowed the separation from the mother liquors of small brown crystals identified on the basis of X-ray analysis as the already known complex of formula [(dpp)PdI2] ("py-py" coordination), this result once again outlining the tendency of dhdpp to be dehydrogenated to dpp.

Characterization of tetrakis(thiadiazole)porphyrazine metal complexes by magnetic circular dichroism and magnetic circularly polarized luminescence.

The magnetic circular dichroism (MCD) spectra of metal complexes of tetrakis(thiadiazole)porphyrazines ([TTDPzM] with M = 2HI , ZnII , MgII (H2 O), and CdII ) have been recorded in dimethyl formamide solution. Together with the UV-Vis spectra, the MCD spectra provide useful information about the structure and electronic properties of the complexes. The experimental UV-Vis and MCD spectra compare pretty well with DFT calculations of two sorts, based either on the sum-over-states (SOS) approach or on the complex polarization propagator approach. They further corroborate the findings and interpretation of MCD spectra of porphyrazines based on the model of Michl for peripheral molecular orbitals. Magnetic circularly polarized luminescence (MCPL) spectra, quite uncommon in the literature, have been recorded for [TTDPzM] (M = 2HI , ZnII , MgII (H2 O)).

Tetra-2,3-pyrazinoporphyrazines with Peripherally Appended Pyridine Rings. 20. Mono- and Pentanuclear AlIII and GaIII Complexes: Synthesis and Physicochemical and Photoactivity Studies.

The autocyclotetramerization of the precursor 2,3-dicyano-5,6-di(2'-pyridyl)pyrazine [(CN)2Py2Pyz] in the presence of MCl3 compounds (M = AlIII, GaIII) leads to the formation of the new mononuclear porphyrazine complexes [Py8TPyzPzMCl]·xH2O (Py8TPyzPz = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion). From these species, the hydroxide analogues [Py8TPyzPzMOH]·xH2O were obtained by contact with hot water, and their corresponding pentanuclear species [(PdCl2)4Py8TPyzPzMCl]·xH2O could be easily formed by the reaction with PdCl2. Physicochemical characterization of the mono- and pentanuclear macrocycles was based on elemental analysis, and mass, powder X-ray, and IR spectra. UV-vis spectral studies of the mononuclear species in solutions of DMF, DMSO, or pyridine (c ≈ 10-5-10-6 M) indicate (mainly in DMF and DMSO) the initial presence of aggregation, in some cases accompanied by the concomitant occurrence for the complex of a one-electron reduction. While disaggregation into a single species evolves spontaneously over time, the -1 charged species, eventually also found present, can be brought back to its neutral form by addition of a slight amount of HCl, the final spectrum showing the presence of the starting neutral species in its pure monomeric form. Similar aspects were faced also for the parent pentanuclear complexes. Cyclic voltammetry experiments, conducted for the mono-/pentanuclear complexes in DMF and DMSO (c ≈ 10-4 M), exhibit progressive one-electron reductions (1 → 4) characterized by E1/2 values (V vs SCE) positioned to significantly less negative values than those known for the phthalocyanine (Pc) analogues, these data confirming the previously already proven higher electron-deficient character of the MII derivatives of the Py8TPyzPz macrocycle with respect to Pc. The role of the present new series of AlIII and GaIII macrocyclic species to act as photosensitizers for the generation of singlet oxygen, 1O2, the cytotoxic agent in the anticancer treatment known as photodynamic therapy (PDT), has been explored in DMF/HCl. Among the quantum yields ΦΔ, the value found for the GaIII complex [Py8TPyzPzGaCl] (0.68), practically coincident with that observed for the TTDPz analogue (0.69), is well above those of most porphyrazines analogues (ΦΔ = 0.4-0.6), a result encouraging further research work for potential applications in the biochemical field.

Tetra-2,3-pyrazinoporphyrazines with Peripherally Appended Pyridine Rings. 19. Pentanuclear Octa(2-pyridyl)tetrapyrazinoporphyrazines Carrying Externally Carboranthiolate Groups: Physicochemical Properties and Potentialities as Anticancer Drugs.

New pentanuclear porphyrazine complexes of formula [{Pd(CBT)2}4LM]· xH2O (L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion, CBT = m-carborane-1-thiolate, and M = MgII(H2O), ZnII, PdII) were prepared in good yield as dark green hydrated amorphous solids by reaction of the respective pentanuclear species [(PdCl2)4LM] with m-carboran-1-thiol in CH3CN. Physicochemical characterization of the new species was carried out by elemental and thermogravimetric analysis along with IR and 1H/13C NMR measurements. UV-vis spectral characterization performed in DMSO, DMF, and pyridine solution provided information about the stability of the new homo/heteropentanuclear species and their tendency to undergo detachment of the peripheral Pd(CBT)2 groups. The data from NMR, UV-vis, and electrochemical experiments indicate that external coordination of the Pd(CBT)2 units to the mononuclear [LM] species affects only slightly the π electron distribution within the internal macrocyclic choromophore. The Pd(CBT)2 units are released in pyridine solution and in the case of the ZnII complex [{Pd(CBT)2}4LZn] give rise to a finely crystalline light-yellow solid identified by single-crystal X-ray work as the trans isomer of the bispyridine adduct [py2(CBT)2Pd]. The new pentanuclear macrocyclic complexes behave in DMF solution as active photosensitizers for singlet oxygen production, 1O2, the cytotoxic agent in anticancer photodynamic therapy, and have larger quantum yield values (ΦΔ = 0.6-0.7) than those found on average for the related tetrapyrazinoporphyrazine analogs (ΦΔ = 0.4-0.6). The presence of the CBT groups in the currently investigated complexes opens up the possibility for their use in boron neutron capture therapy, leading potentially to new bimodal anticancer curative drugs.

A Phthalocyanine-ortho-Carborane Conjugate for Boron Neutron Capture Therapy: Synthesis, Physicochemical Properties, and in vitro Tests.

Boronated molecular systems can be applied to boron neutron capture therapy (BNCT). Among these systems, carborane-containing phthalocyanines (Pcs) are the most promising BNCT agents. Herein we report the new zinc (II) complex of the hexacationic Pc 6, which has been obtained as iodide salt through quaternization of the neutral precursor with methyl iodide. Compound 6 was synthesized over a sequence of four steps. The complex, and its precursors as well, were characterized by a combination of spectroscopic techniques, and their structures assessed by 1 H, 13 C, 11 B, and two-dimensional NMR spectroscopy experiments. Together with a marked tendency to aggregate, 6 showed appreciable solubility in water. Singlet oxygen quantum yield (ΦΔ ) of 0.38, and fluorescence quantum yield (ΦF ) of 0.13 were obtained for 6 in a DMF solution. The complex proved to be very effective in enriching UMR-106 cells with 10 B, showing very good performance even in case of very low concentrations exposure, i. e. 1 ppm, that moreover resulted in a mild cytotoxic effect. Such a feature can be related to the polycationic nature of the complex, and hence to the well-known propensity of positively charged species to enter the cellular membrane or to adhere to its external surface.

Photoactivity of New Octacationic Magnesium(II) and Zinc(II) Porphyrazines in a Water Solution and G-Quadruplex Binding Ability of Differently Sized Zinc(II) Porphyrazines.

The new octacations [(2-Mepy)8PzM]8+ [M = MgII(H2O), ZnII], isolated as iodide salts, were obtained from the corresponding neutral complexes [Py8PzM] (Py = 2-pyridyl; Pz = porphyrazinato dianion) upon quaternization with CH3I of the N atoms of the 2-pyridyl rings under mild experimental conditions. The absorption spectra registered in organic solvents as well as in water (H2O) confirm the presence of the complexes in their monomeric form in all cases. The two octacations behave as photosensitizers in a H2O/sodium dodecyl sulfate solution for the production of singlet oxygen, 1O2, and exhibit quantum yield values (ΦΔ) 2.2-2.5 higher than those measured for the standard PcAlSmix, a promising feature of interest for photodynamic therapy. The interaction of the ZnII octacation [(2-Mepy)8PzZn]8+ with different types of DNA has been studied by means of optical spectroscopic techniques, clearly suggesting that binding of the charged macrocycle to the DNA effectively takes place. In order to assess the effect of the aromatic ring size, the same binding study was performed for the octapyridinated zinc(II) tetraquinoxalinoporphyrazine complex having a much more expanded macrocyclic framework and compared with the behavior of the parent octapyridinated zinc(II) tetrapyrazinoporphyrazine complex having an intermediate macrocycle. The achieved information confirms the relationship between the binding of the charged macrocycle to the DNA and the dimension of the porphyrazine macrocycle.

Octakis(2-pyridyl)porphyrazine and Its Neutral Metal Derivatives: UV-Visible Spectral, Electrochemical, and Photoactivity Studies.

Tetrapyrrolic porphyrazine macrocycles with externally appended 2-pyridyl rings were synthesized and characterized as to their spectroscopic, electrochemical, and photophysical properties. The investigated compounds are represented as [Py8PzH2], the unmetalated octakis(2-pyridyl)porphyrazine, and the metal complexes [Py8PzM], where M is MgII(H2O), CuII, ZnII, or CoII. The spectroscopic properties and the electrochemical behavior of these compounds were examined in solution of polar (pyridine, dimethyl sulfoxide, and dimethylformamide) and nondonor solvents (CHCl3, CH2Cl2), and the data were compared with those obtained from earlier studies on the related tetrapyrazinoporphyrazines, [Py8TPyzPzM], and the tetraquinoxalinoporphyrazines, [Py8QxPzM], also bearing externally 2-pyridyl rings, and characterized by a more extended central π-conjugated macrocyclic framework. The newly synthesized porphyrazines possess good solubility and are present in their monomeric form in all the examined solvents as shown by UV-visible spectra. The unmetalated species and metal derivatives undergo multiple one-electron reductions within the potential range of the nonaqueous examined solvents. The derivatives with nonredox active metal centers could accept four electrons on the conjugated macrocycle, while the CoII complex was characterized by a single one-electron oxidation and five reductions in DMSO. The photosensitizer activity for the generation of singlet oxygen was also examined for the MgII(H2O) and ZnII complexes in DMF, with measured ΦΔ values being, respectively, 0.42 and 0.64, this latter value indicating the ZnII species as being a promising material for use as anticancer agent in photodynamic therapy.

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 17. Photosensitizing properties and cellular effects of ZnII octacationic and ZnII/PtII hexacationic macrocycles in aqueous media: Perspectives of multimodal anticancer potentialities.

The photosensitizing activity of two multiply charged porphyrazine derivatives, i.e. the ZnII species [(CH3)8LZn]8+ and the ZnII/PtII heterobimetallic complex [(PtCl2)(CH3)6LZn]6+ (neutralized byI- ions; L=tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato dianion) has been examined in the water medium in the presence of SDS under experimental conditions in which the two species are present exclusively in their monomeric form. The determined quantum yield values (ΦΔ) for both complexes, of interest in photodynamic therapy (PDT), are 2.3-2.5 higher than that of the aluminium compound PcAlSmix (Photosens®) used as the reference standard, an encouraging result for the application of the two cationic species as anticancer curative drugs in PDT. Investigation was also extended to explore the cellular effects on the melanoma C8161 and the oral squamous carcinoma CA-1 cell lines like viability, cellular uptake, cell death modality and cell cycle distribution experiments. The IC50 values for the ZnII and ZnII/PtII cations are consistently lower than those of the reference standard, thus the degree of efficiency as anticancer agents being in the order octacation≫hexacation>PcAlSmix. A large prevalence of apoptosis with respect to necrosis is observed for both charged complexes. Thus, all achieved information from photoactivity and in vitro tests in water solution further enhance perspectives for the application of the two ZnII cation [(CH3)8LZn]8+ and the related ZnII/PtII analog [(PtCl2)(CH3)6LZn]6+ as potential bi-multimodal anticancer drugs.

Water-soluble carboranyl-phthalocyanines for BNCT. Synthesis, characterization, and in vitro tests of the Zn(II)-nido-carboranyl-hexylthiophthalocyanine.

The zinc(II) complex of the octa-anionic 2,3,9,10,16,17,23,24-octakis-(7-methyl-7,8-dicarba-nido-undeca-boran-8-yl)hexyl-thio-6,13,20,27-phthalocyanine (nido-[ZnMCHESPc]Cs8, 7) has been obtained in the form of caesium salt through mild deboronation of the neutral precursor, the closo-[ZnMCHESPc] complex, 6, with CsF. 6 has been synthesized, in turn, by heating a finely ground mixture of the appropriate phthalonitrile and zinc(II) acetate at 180.0 °C. The complexes have been characterized by elemental analyses, FT-IR, UV-visible absorption and fluorescence emission spectroscopy, and their structures were assessed by (1)H, (13)C, (11)B, and two-dimensional homo- and hetero-correlated NMR spectroscopy experiments. 7 showed appreciable solubility in water solution, together with a marked tendency to aggregate. Aggregation of 7 in the hydrotropic medium resulted in significant fluorescence quenching. Instead, fluorescence quantum yields (Φ(F)) of 0.14 and 0.08, and singlet oxygen quantum yields (Φ(Δ)) of 0.63 and 0.24 were obtained for 6 and 7, respectively, in a DMF solution. In vitro boron neutron capture therapy (BNCT) experiments, employing boron imaging techniques as implemented in qualitative and quantitative neutron autoradiography methods, showed that 7 is capable of increasing the boron concentration of two selected cancerous cell lines, the DHD/K12/TRb of rat colon adenocarcinoma and UMR-106 of rat osteosarcoma, with the large-size Cs(+) counter-ions used to neutralize the negatively charged carborane polyhedra not presenting a significant obstacle to the process. Taken together, BNCT and photophysical measurement results indicated that 7 is potentially suitable for bimodal or multimodal anticancer therapy.

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 15. Effects of the pyridyl substituents and fused exocyclic rings on the UV-visible spectroscopic properties of Mg(II)-porphyrazines: a combined experimental and DFT/TDDFT study.

Two new Mg(II) porphyrazine macrocycles, the octakis(2-pyridyl)porphyrazinato-magnesium(II), [Py8PzMg(H2O)], and the tetrakis-[6,7-di(2-pyridyl)quinoxalino]porphyrazinato-magnesium(II), [Py8QxPzMg(H2O)], were prepared by Mg-template macrocyclization processes, and their general physicochemical properties were examined. The previously reported porphyrazine analog, the tetrakis-2,3-[5,6-di(2-pyridyl)-pyrazino]porphyrazinato-magnesium(II), [Py8PyzPzMg(H2O)], has been also considered in the present work. The UV-visible solution spectra in nonaqueous solvents of this triad of externally octapyridinated Mg(II) complexes exhibit the usual profile observed for phthalocyanine and porphyrazine macrocycles, with intense absorptions in the Soret (300-450 nm) and Q band (600-800 nm) regions. It is observed that the Q band maximum sensibly shifts toward the red with peak values at 635 → 658 → 759 nm along the series [Py8PzMg(H2O)], [Py8PyzPzMg(H2O)], and [Py8QxPzMg(H2O)], as the extension of the macrocycle π-system increases. TDDFT calculations of the electronic absorption spectra were performed for the related water-free model compounds [Py8PzMg], [Py8PyzPzMg], and [Py8QxPzMg] to provide an interpretation of the UV-visible spectral changes occurring upon introduction of the pyrazine and quinoxaline rings at the periphery of the Pz macrocycle. To discriminate the electronic effects of the fused exocyclic rings from those of the appended 2-pyridyl rings, the UV-visible spectra of [PzMg] and [PyzPzMg] were also theoretically investigated. The theoretical results prove to agree very well with the experimental data, providing an accurate description of the UV-visible spectra. The observed spectral changes are interpreted on the basis of the electronic structure changes occurring along the series.

Pyrazinoporphyrazines with externally appended pyridine rings. 13. Structure, UV-visible spectral features, and noncovalent interaction with DNA of a positively charged binuclear (Zn(II)/Pt(II)) macrocycle with multimodal anticancer potentialities.

We investigated with spectroscopic techniques the noncovalent interaction of a bimetallic water-soluble (Zn(II)/Pt(II)) porphyrazine hexacation, [(PtCl(2))(CH(3))(6)LZn](6+), and its octacationic analogue [(CH(3))(8)LZn](8+), lacking the cis-platin-like functionality, with a 21-mer double strand (ds) 5'-d[GGG(TTAGGG)(3)]-3'/3'-d[CCC(AATCCC)(3)]-5', as model for B-DNA. Both hexacation and octacation tend to aggregate in water. The structure as well as the ground and excited-state electronic properties of the Zn(II)/Pt(II) hexacation [(PtCl(2))(CH(3))(6)LZn](6+) in water solution were investigated using density functional theory (DFT) and time-dependent DFT (TDDFT) methods. TDDFT calculations of the lowest excited states of [(PtCl(2))(CH(3))(6)LZn](6+) in water provided an accurate description of the Q-band spectral region. In particular, the calculated optical spectra were in agreement with the experimental ones, obtained in the presence of micelles favoring complete disruption of the aggregates. The model for dsDNA binding that emerges from the analysis of UV-vis absorption and time-resolved fluorescence data shows the presence of complexes of 1 dsDNA molecule with 1, 2, and 4 macrocycles. Comparing the results for the hexacation [(PtCl(2))(CH(3))(6)LZn](6+) with those for the [(CH(3))(8)LZn](8+)octacation, we observed a higher degree of monomerization for the [(PtCl(2))(CH(3))(6)LZn](6+) derivative.

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 12. New heteropentanuclear complexes carrying four exocyclic cis-platin-like functionalities as potential bimodal (PDT/cis-platin) anticancer agents.

Heteropentanuclear porphyrazines having the formula [(PtCl2)4LM] where L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato dianion and M = Zn(II), Mg(II)(H2O), Pd(II), Cu(II) or Co(II) were characterized by elemental analyses, IR-UV-visible spectroscopy and electrochemistry and the data compared to new and previously published results for the corresponding homopentanuclear compound [(PtCl2)4LPt]. This latter species has four external N2(py)PtCl2 coordination sites which closely resemble cis-platin, (NH3)2PtCl2, the potent chemotherapeutic anticancer drug, and is able to act as a photosensitizer for the generation of (1)O2, the cytotoxic agent in photodynamic therapy (PDT). UV-visible spectra and half wave potentials for reduction of [(PtCl2)4LM], [(PtCl2)4LPt], the parallel series of mononuclear [LM] compounds and the pentanuclear [(PdCl2)4LM] compounds were examined in the nonaqueous solvents dimethyl sulfoxide, pyridine, and dimethylformamide. The complete set of available data indicate that external coordination of the PtCl2 and PdCl2 units significantly increases the level of the electron-deficiency of the entire molecular framework despite the fact that these groups are far away from the central porphyrazine π-ring system and have coordination sites nearly orthogonal to the plane of the macrocycle. The pentanuclear species [(M'Cl2)4LM] (M' = Pt(II), Pd(II)) undergo multiple one-electron transfers and exhibit an easier reducibility as compared to related electrode reactions of the parent compounds [LM] having the same central metal. Aggregation phenomena and reducibility of the porphyrazines to their monoanionic form (prevalently in DMF) are observed for some of the examined compounds and were analyzed and accurately taken into account. Quantum yields of (1)O2 (ΦΔ), of interest in PDT, were measured for [(PtCl2)4LM] with M = Zn(II), Mg(II)(H2O), or Pd(II) and the related macrocycles [(PdCl2)4LM] and [LM] in dimethylformamide (DMF) and/or DMF preacidified with HCl (DMF/HCl, [HCl]: 1-2 × 10(-4) M). Excellent ΦΔ values (0.5-0.6) which qualify the compounds as potent photosensitizers in PDT were obtained for the pentanuclear species having Zn(II) or Pd(II) as central metal ions. The [(PtCl2)4LZn] and [(PtCl2)4LPd] complexes are of special interest as potential bimodal anticancer agents because of the incorporated four cis-platin-like functionalities.

Tetrakis(thiadiazole)porphyrazines. 8. Singlet oxygen production, fluorescence response and liposomal incorporation of tetrakis(thiadiazole)porphyrazine macrocycles [TTDPzM] (M = Mg(II)(H2O), Zn(II), Al(III)Cl, Ga(III)Cl, Cd(II), Cu(II), 2H(I)).

The photoactivity for the generation of singlet oxygen, (1)O(2), the key cytotoxic agent in the anticancer treatment known as photodynamic therapy (PDT), and the fluorescence response of the highly electron-deficient tetrakis(thiadiazole)porphyrazines of formula [TTDPzM] (M = Mg(II)(H(2)O), Zn(II), Al(III)Cl, Ga(III)Cl, Cd(II), Cu(II), 2H(I)) were examined (c ≅ 10(-5) M) in dimethylformamide (DMF) and/or in DMF preacidified with HCl (DMF/HCl; [HCl] = 1-4 × 10(-4) M). The singlet oxygen quantum yield (Φ(Δ)) of all the compounds was determined by using a widely employed procedure based on the selective oxidation of the 1,3-diphenylisobenzofuran (DPBF), modified in part as reported. The list of the Φ(Δ) values indicates excellent photosensitizing properties for the series of compounds carrying "closed shell" metal ions, with values measured in DMF/HCl respectful of the "heavy atom effect" for the first four lighter centers, increasing in the order Mg(II) < Al(III) < Zn(II) < Ga(III). Data of Φ(Δ) concerning the unmetalated species [TTDPzH(2)], present in solution in the form of the corresponding anion [TTDPz](2-), and the Cd(II) and Cu(II) complexes are also presented and discussed. Extensive discussion is also developed on the fluorescence quantum yield values Φ(F), with data on the Mg(II) and Al(III) compounds in DMF/HCl (0.44 and 0.53, respectively) indicative of promising perspectives for applications in fluorescence imaging techniques. The Φ(F) data of the studied porphyrazine series, Φ(F)(Pz), correlate linearly with those of the homologous phthalocyaninato complexes, Φ(F)(Pc), suggesting a closely similar behaviour between the two classes of compounds. The incorporation of [TTDPzZn] into liposomes was successfully achieved following the detergent depletion method (DDM) from a mixed micellar solution by means of gel-filtration. Retention of [TTDPzZn] (~40%) in its photoactive monomeric form into liposomes is proved by absorption and fluorescence spectra, this proposing the Zn(II) complex as a promising candidate for use in PDT.

Structural flexibility and role of vicinal 2-thienyl rings in 2,3-dicyano-5,6-di(2-thienyl)-1,4-pyrazine, [(CN)2Th2Pyz], its palladium(II) complex [(CN)2Th2Pyz(PdCl2)2], and the related pentametallic pyrazinoporphyrazines [(PdCl2)4Th8TPyzPzM] (M = Mg(II)(H2O), Zn(II)).

The solid state and solution structure of 2,3-dicyano-5,6-di(2-thienyl)-1,4-pyrazine, [(CN)(2)Th(2)Pyz], and its Pd(II) derivative, [(CN)(2)Th(2)Pyz(PdCl(2))(2)]·H(2)O, formed by reaction of [(CN)(2)Th(2)Pyz] with [(C(6)H(5)CN)(2)PdCl(2)] were characterized by X-ray, UV-visible, (1)H and (13)C NMR, and extended X-ray absorption fine structure (EXAFS) spectral measurements. The X-ray crystal structure of [(CN)(2)Th(2)Pyz] shows the presence of one thienyl ring positioned orthogonal to the rest of the molecule, with the two vicinal thienyl rings lying orthogonal to each other in a rare arrangement. NMR studies of [(CN)(2)Th(2)Pyz] in the solid state and in solutions of dimethylformamide or dimethyl sulfoxide confirm a nonequivalence of the thienyl rings in the solid state and also in solution. EXAFS results indicate that two distinct Pd(II) coordination sites are formed at the di(2-thienyl)pyrazino moiety of [(CN)(2)Th(2)Pyz(PdCl(2))(2)]·H(2)O, with identical Pd-N(pyz) (2.03(3) Å) and Pd-Cl (2.36(3) Å) bond lengths but with different Pd-S1 (2.25(4) Å) and Pd-S2 (3.21(5) Å) bond distances in an overall asymmetric molecular framework. Density functional theory (DFT) and time-dependent DFT (TDDFT) theoretical studies also provide information about the structure and spectral behavior of the precursor and its metalated Pd(II) derivative. (1)H/(13)C NMR and UV-visible spectral measurements were also carried out on two heteropentametallic porphyrazine macrocycles which were prepared by a reaction of PdCl(2) with [Th(8)TPyzPzM] where Th(8)TPyzPz = tetrakis-2,3-[5,6-di-(2-thienyl)-pyrazino]porphyrazinato dianion and M = Mg(II)(H(2)O) or Zn(II). Spectroscopic data on the newly synthesized [(PdCl(2))(4)Th(8)TPyzPzM] compounds suggest that the binding of PdCl(2) involves coordination sites of the type S(2(th))PdCl(2) with the two thienyl rings of each di(2-thienyl)pyrazino fragment bound to Pd(II) in an equivalent manner ("th-th" coordination). This is similar to what was found for the corresponding octapyridinated analogues ("py-py" coordination).

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 9. Novel heterobimetallic macrocycles and related hydrosoluble hexacations as potentially active photo/chemotherapeutic anticancer agents.

New homo- and heterobimetallic porphyrazine complexes of general formula [(M'Cl(2))LM] (L = tetrakis-2,3-[5,6-di-(2-pyridyl)pyrazino]porphyrazinato dianion), with M = Zn(II), Mg(II)(H(2)O), or Pd(II) in the central cavity and one M'Cl(2) unit (M' = Pd(II), Pt(II)) peripherally coordinated at the pyridine N atoms of one of the dipyridinopyrazine fragments, were prepared and characterized by elemental analyses and IR/UV-visible spectroscopy. Related water-soluble salt-like species, carrying the hexacations [(PtCl(2))(CH(3))(6)LM](6+) (neutralized by I(-) ions), were also prepared and similarly characterized. Retention of clathrated water molecules is a common feature of all the compounds. A detailed (1)H and (13)C NMR investigation in dimethylformamide (DMF-d(7)) and dimethyl sulfoxide (DMSO-d(6)) provided useful information on the type of arrangement in the neutral and hexacationic species of the metalated dipyridinopyrazine fragments, in which the metal centers (Pd(II)/Pt(II)) are bound to the pyridine N atoms ("py-py" coordination) with formation of N(2(pyr))PdCl(2) or N(2(pyr))PtCl(2) coordination sites, the latter one featuring a cis-platin-like functionality. Data obtained in DMF solution of the quantum yield (Φ(Δ)) for the generation of singlet oxygen, (1)O(2), the cytotoxic agent in photodynamic therapy (PDT), indicate that all the neutral and charged complexes, among them particularly those carrying centrally Zn(II) or Pd(II), exhibit excellent photosensitizing properties, this qualifying the externally platinated complexes as potential bimodal PDT/chemotherapeutic anticancer agents. Fluorescence data (Φ(F)) provided additional information on the photoactivity of all the species studied. The following companion paper describes the observed interaction of the Zn(II) hexacation [(PtCl(2))(CH(3))(6)LZn](6+) with a G-quadruplex (G4) structure of the telomeric DNA sequence 5'-d[AGGG(TTAGGG)(3)]-3' in water.

Tetra-2,3-pyrazinoporphyrazines with externally appended thienyl rings: synthesis, UV-visible spectra, electrochemical behavior, and photoactivity for the generation of singlet oxygen.

A series of pyrazinoporphyrazine macrocycles carrying externally appended 2-thienyl rings, represented as [Th(8)TPyzPzM], where Th(8)TPyzPz = tetrakis-2,3-[5,6-di(2-thienyl)pyrazino]porphyrazinato anion and M = Mg(II)(H(2)O), Zn(II), Co(II), Cu(II), or 2H(1), were prepared and isolated as solid air-stable hydrated species. All of the compounds, completely insoluble in water, were characterized by their UV-visible spectra and electrochemical behavior in solutions of dimethylformamide (DMF), dimethyl sulfoxide, and pyridine. Molecular aggregation occurs at concentrations of ca. 10(-4) M, but monomers are formed in more dilute solutions of 10(-5) M or less. The examined octathienyl compounds [Th(8)TPyzPzM] behave as electron-deficient macrocycles, and UV-visible spectral measurements provide useful information about how the peripheral thienyl rings influence the electronic distribution over the entire macrocyclic framework. Cyclic voltammetric and spectroelectrochemical data confirm the easier reducibility of the compounds as compared to the related phthalocyanine analogues, and the overall redox behavior and thermodynamic potentials for the four stepwise one-electron reductions of the compounds are similar to those of the earlier examined octapyridinated analogues [Py(8)TPyzPzM]. Quantum yields (Φ(Δ)) for the generation of singlet oxygen, (1)O(2), the cytotoxic agent active in photodynamic therapy (PDT), and fluorescence quantum yields (Φ(F)) were measured for the Zn(II) and Mg(II) complexes, [Th(8)TPyzPzZn] and [Th(8)TPyzPzMg(H(2)O)], and the data were compared to those of corresponding octapyridino macrocycles [Py(8)TPyzPzZn] and [Py(8)TPyzPzMg(H(2)O)] and their related octacations [(2-Mepy)(8)TPyzPzZn](8+) and [(2-Mepy)(8)TPyzPzMg(H(2)O)](8+). These measurements were carried out in DMF and in DMF preacidified with HCl (ca. 10(-4) M). All of the examined Zn(II) compounds behave as excellent photosensitizers (Φ(Δ) = 0.4-0.6) both in DMF and DMF/HCl solutions, whereas noticeable fluorescence activity (Φ(F) = 0.36-0.43) in DMF/HCl solutions is shown by the Mg(II) derivatives; these data might provide perspectives for applications in PDT (Zn(II)) and imaging response and diagnosis (Mg(II)).