Dioxepine-Peri-Annulated PMIs-Synthesis and Spectral and Sensing Properties.

New perylene monoimide (PMI) derivatives bearing a seven-membered heterocycle and 1,8-diaminosarcophagine (DiAmSar) or N,N-dimethylaminoethyl chelator fragments were synthesized, and their spectroscopic properties in the absence and presence of metal cations were determined to evaluate their potential applications as PET optical sensors for such analytes. DFT and TDDFT calculations were employed to rationalize the observed effects.

13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization.

Tautomerization of 2-phenylimidazolecarbaldehydes has not been studied in detail so far, although this process is a well-known phenomenon for imidazole derivatives. That is why we focus our study on a series of 2-phenylimidazolecarbaldehydes and their parent alcohols that were synthesized and studied by detailed 1H and 13C NMR in solution and in the solid state. The apparent problem is that the fast tautomerization impedes the full structural description of the compounds by conventional 13C NMR measurements. Indeed, the 13C NMR spectra in solution exhibit poor resolution, and in most cases, signals from the imidazole ring are not detectable. To avoid this problem, we used 13C CP-MAS NMR as an alternative spectroscopic method for unambiguous spectroscopic characterization of the studied series of 2-phenylimidazoles. The data were analyzed in combination with quantum chemical DFT-GIAO methods by considering the tautomerization process and the intermolecular interactions. The DFT (B3LYP/6-31G(d,p)) calculations allowed to identify and suggest the preferred tautomer in the gas phase and in DMSO solvent, which for alcohols are (2-phenyl-1H-imidazol-4-yl)methanol and its analogs, and for the aldehydes are the 2-phenyl-1H-imidazole-5-carbaldehydes. The gas-phase calculated energy differences between the two possible tautomeric forms are in the range 0.645-1.415 kcal/mol for the alcohols and 2.510-3.059 kcal/mol for the aldehydes. In the DMSO solvent, however, for all compounds, the calculated energy differences go below 1.20 kcal/mol. These data suggest that both tautomeric forms of the studied 2-phenylimidazoles can be present in solution at room temperature. Our data from detailed 2D NMR measurements in the solid state (1H-13C HETCOR and 1H-1H double-quantum coherence MAS NMR) suggested that also in the solid state both tautomers coexist in different crystalline domains. This fact does not obscure the 13C CP-MAS NMR spectra of the studied 2-phenyl substituted imidazoles and suggests this spectroscopic method as a powerful tool for a complete structural description of tautomeric systems with aromatic conjugation.

Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines.

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.

Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity.

Research on platinum-based anticancer drugs continuously strives to develop new non-classical platinum complexes. Pt(IV) prodrugs are the most promising, and their activation-by-reduction mechanism of action is being explored as a prospect for higher selectivity and efficiency. Herein, we present the anticancer potency and chemical reactivity of Pt(IV) complexes formed by linking pyrene butyric acid with cisplatin. The results from cytotoxicity screening on 10 types of cancer cell lines and non-malignant cells (HEK-293) indicated IC50 values as low as 50-70 nM for the monosubstituted Pt(IV) complex against leukemia cell lines (HL-60 and SKW3) and a cisplatin-resistant derivative (HL-60/CDDP). Interestingly, the bis-substituted complex is virtually non-toxic to both healthy and cancerous cells of adherent types. Nevertheless, it shows high cytotoxicity against multidrug-resistant derivatives HL-60/CDDP and HL-60/Dox. The reactivity of the complexes with biological reductants was monitored by the NMR method. Furthermore, the platinum uptake by the treated cells was examined on two types of cellular cultures: adherent and suspension growing, and proteome profiling was conducted to track expression changes of key apoptosis-related proteins in HL-60 cells. The general conclusion points to a possible cytoskeletal entrapment of the bulkier bis-pyrene complex that could be limiting its cytotoxicity to adherent cells, both cancerous and healthy ones.

Enhanced cellular uptake of platinum by a tetracationic Pt(II) nanocapsule and its implications to cancer treatment.

Despite the known limitations of cisplatin chemotherapy, the treatment of cancer by platinum-based drugs remains the method of choice for many oncologists. The advancement in drug delivery formulations and protocols of combined treatments provided effective tools to ameliorate the side effects of platinum-based therapies. Another approach to improve the pharmacological profiles of anticancer platinum drugs is to properly modify their structure and composition, which has produced numerous platinum complexes with improved therapeutic effect. Recently, we have demonstrated the strong anticancer potency of supramolecular nanocapsules that form by self-assembly of four bis-anthracene ligands with two metal ions, either Pt(II) or Pd(II). Herein, we focus our study on the Pt(II) nanocapsule and its uptake by two types of cancer cells, suspension cultures of HL-60 cells and the adherent cancer cells HT-29. Comparison of the platinum uptake by cancer cells treated with the nanocapsule and with cisplatin evidenced superior uptake of platinum caused by the nanocapsule, which in HT-29 and HL-60 cells prevails by 21 and 31 times, respectively. Morphological changes in the HL-60 cells induced by the Pt(II) nanocapsule were studied by transmission electron microscopy (TEM) which provided plausible explanation of the uptake results. These data corroborate also with the known nanocapsule's very high cytotoxicity, better selectivity, and lack of cross-resistance with cisplatin. Additionally, our estimations of the drug-drug interactions in combined treatments established the propensity of the nanocapsule to exert supra-additive cytotoxicity in combination with cisplatin against the bladder cancer T-24 cells. All these findings define the scope for more detailed pharmacological characterization of the presented Pt(II) nanocapsule.

Biomedical Applications of Metallosupramolecular Assemblies-Structural Aspects of the Anticancer Activity.

The design and development of metallosupramolecular systems has resulted in construction of a myriad of fascinating structures with highly diverse properties and potential applications. Assessment of the biomedical applications of metallosupramolecular assemblies is an emerging field of research that stems from the recently demonstrated promising results on such systems. After the pioneering works of Therrien and coworkers on organometallic Ru-cages with promising anticancer properties, this topic has evolved to the more recent studies on bioactivity of supramolecular coordination complexes built from different metal ions and various multidentate ligands. Sufficient amount of data on the anticancer activity of metallosupramolecules has already been reported and allows outlining some general tendencies in the structural aspects of the biological activity. The main structural properties of the complexes that can be readily modified to enhance their activity are the size, the shape and charge of the formed complexes. Moreover, the intrinsic properties of the building components could predetermine some of the main characteristics of the overall supramolecular complex, such as its optical properties, chemical reactivity, solubility, etc., and could, thereby, define the areas of its biomedical applications. The unique structural property of most of the metallosupramolecular assemblies, however, is the presence of a discrete cavity that renders a whole range of additional applications resulting from specific host-guest interactions. The encapsulations of small bioactive or fluorescent molecules have been employed for delivery or recognition purposes in many examples. On the other hand, metallosupramolecules have been imbedded into target-specific polymeric nanoparticles that resulted in a successful combination of their therapeutic and diagnostic properties, making them promising for theranostic application in cancer treatment. The aim of this review paper is to mark out some key tendencies in the reported metallosupramolecular structures in relation with their biological activity and potential areas of biomedical application. In this way, a useful set of guidelines can be delineated to help synthetic chemists broaden the application areas of their supramolecular systems by few structural changes.

Copper radiopharmaceuticals for theranostic applications.

The growing advancement in nuclear medicine challenges researchers from several different fields to integrate imaging and therapeutic modalities in a theranostic radiopharmaceutical, which can be defined as a molecular entity with readily replaceable radioisotope to provide easy switch between diagnostic and therapeutic applications for efficient and patient-friendly treatment of diseases. For such a reason, the diagnostic and therapeutic potential of all five medical radionuclides of copper have thoroughly been investigated as they boost the hope for development of successful radiotheranostics. To facilitate the mutual understanding between all different specialists working on this multidisciplinary field, we summarized the recent updates in copper-based nuclear medicine, with specific attention to the potential theranostic applications. Thereby, this review paper is focused on the current achievements in the copper-related complementary fields, such as synthetic and nuclear chemistry, biological assessment of radiopharmaceuticals, design and development of nanomaterials for multimodal theranostic implications. This work includes: i) description of available copper radionuclide production methods; ii) analyses of the synthetic strategies for development of improved copper radiopharmaceuticals; iii) summary of reported clinical data and recent preclinical studies from the last five years on biological applicability of copper radiopharmaceuticals; and iv) illustration of some sophisticated multimodal nanotheranostic agents that comprise several imaging and therapeutic modalities. Significant advancement can be seen in the synthetic procedures, which enables the broader implication of pretargeting approaches via bioorthogonal click reactions, as well as in the nanotechnology methods for biomimetic construction of biocompatible multimodal copper theranostics. All this gives the hope that personalized treatment of various diseases can be achieved by copper theranostics in the near future.

Anticancer Potencies of Pt(II) - and Pd(II)-linked M2L4 Coordination Capsules with Improved Selectivity.

Pt(II) - and Pd(II)-linked M2 L4 coordination capsules, providing a confined cavity encircled by polyaromatic frameworks, exhibit anticancer activities superior to cisplatin against two types of leukemic cells (HL-60 and SKW-3) and pronounced toxicity against cisplatin-resistant cells (HL-60/CDDP). Notably, the cytotoxic selectivities of the Pt(II) and Pd(II) capsules toward cancerous cells are up to 5.3-fold higher than that of cisplatin, as estimated through the non-malignant/malignant-cells toxicity ratio employing normal kidney cells (HEK-293). In addition, the anticancer activity of the coordination capsules can be easily altered upon encapsulation of organic guest molecules.

M2L4 coordination capsules with tunable anticancer activity upon guest encapsulation.

Metallosupramolecular cages and capsules have gained increasing popularity as both molecular containers and anticancer agents. For successful combination of these properties a thorough analysis of the effect of guest encapsulation on the host's cytotoxic properties is highly required. Here we report on the cytotoxicity modulation of Pt(ii) and Pd(ii)-linked M2L4 coordination capsules upon encapsulation of guest molecules such as pyrene and caffeine. The anticancer activity of the capsules against various human cancer cells (HT-29, T-24, HL-60 and its resistant counterparts HL-60/Dox and HL-60/CDDP) significantly altered upon the guest encapsulation. The encapsulation of pyrene molecules causes a decrease in the cytotoxicity of the Pt(ii) capsule, which is stronger than that of the Pd(ii) capsule. The cytotoxicities of the caffeine containing capsules are lower than that of the empty capsules (except for HL-60), but still superior to cisplatin under the same conditions. The observed trends in the anticancer activity of the capsules and their host-guest complexes correlate with their different stabilities toward glutathione, estimated by NMR-based kinetic experiments. Mechanistic insights into the observed cytotoxicities are obtained by fluorescence microscopy imaging of tumor cells treated with the capsules and their pyrene complexes. The data suggest the glutathione-triggered disassembly of the capsular structures as a potential activation pathway for their cytotoxicities.

Tautomerism of 4,4'-dihydroxy-1,1'-naphthaldazine studied by experimental and theoretical methods.

BACKGROUND: The title compound belongs to the class of bis-azomethine pigments. On the basis of comparative studies on similar structures, insight into the complex excited state dynamics of such compounds has been gained. It has been shown, for example, that only compounds that possess hydroxyl groups are fluorescent, and that the possibility for cis-trans isomerisation and/or bending motions of the central bis-azomethine fragment allows for different non-radiative decay pathways. RESULTS: The compound, 4,4'-dihydroxy-1,1'-naphthaldazine (1) was synthesized and characterized by means of spectroscopic and quantum chemical methods. The tautomerism of 1 was studied in details by steady state UV-Vis spectroscopy and time resolved flash photolysis. The composite shape of the absorption bands was computationally resolved into individual subbands. Thus, the molar fraction of each component and the corresponding tautomeric constants were estimated from the temperature dependent spectra in ethanol. CONCLUSIONS: According to the spectroscopic data the prevalent tautomer is the diol form, which is in agreement with the theoretical (HF and DFT) predictions. The experimental data show, however, that all three tautomers coexist in solution even at room temperature. Relevant theoretical results were obtained after taking into account the solvent effect by the so-called supermolecule-PCM approach. The TD-DFT B3LYP/6-31 G** calculated excitation energies confirm the assignment of the individual bands obtained from the derivative spectroscopy.

1H, 13C MAS NMR and DFT GIAO study of quercetin and its complex with Al(III) in solid state.

Quercetin (Q) as a pentahydroxy flavonoid, has three possible chelating sites competing in complexation processes. (1)H and (13)C MAS NMR spectra were recorded for solid quercetin and its Al(III) complex (AlQ). (1)H MAS spectrum of quercetin shows a broad resonance at ca. 12 ppm that confirms the existence of intramolecular C5-OH … O=C4 hydrogen bond. Such a signal is absent in the spectrum of AlQ, which is in accordance with other spectroscopic data and the suggested model for the solid-state structure of the complex. DFT GIAO calculations were used to verify the experimental (13)C CPMAS NMR data and to suggest the best model structure for the complex AlQ. The calculated shielding constants for different conformers of isolated quercetin molecules, quercetin trimer as taken from the X-ray data, and different model structures for possible Al(III) complexes were compared with the (13)C CPMAS NMR experimental values. The results demonstrate the importance of intermolecular interactions when dealing with structures in solid state and the successful application of the combined DFT GIAO and (13)C CPMAS NMR approach. All data confirm that the chelating site of Q in the solid complex AlQ involves the deprotonated C5-OH and the C4=O groups at ring C, in contrast to the available studies performed in solution.