Publications

Abstract While photodynamic therapy is known for significant advantages over conventional cancer therapies, its dependence on light has limited it to treating tumors on or just under the skin or on the outer lining of organs/cavities. Herein, we have developed a single-molecule photosensitizer capable of intracellular self-activation and with potential tumor-selectivity due to a chemiluminescent reaction involving only a cancer marker. Thus, the photosensitizer is directly chemiexcited to a triplet excited state capable of generating singlet oxygen, without requiring either a light source or any catalyst/co-factor. Cytotoxicity assays involving the photosensitizer show significant toxicity toward tumor cells, even better than reference drugs, while not inducing toxicity toward normal cells. This work provides a proof-of-concept for a novel type of photosensitizer that eliminates the current restrictions that photodynamic therapy presents regarding tumor size and localization.

Abstract Cancer is a very challenging disease to treat, both in terms of treatment efficiency and side-effects. To overcome these problems, there have been extensive studies regarding the possibility of improving treatment by employing combination therapy, and by exploring therapeutic modalities with reduced side-effects (such as photodynamic therapy (PDT)). Herein, this work has two aims: (i) to develop self-activating photosensitizers for use in light-free photodynamic therapy, which would eliminate light-related restrictions that this therapy currently possesses; (ii) to assess their co-treatment potential when combined with reference chemotherapeutic agents (Tamoxifen and Metformin). We synthesized three new photosensitizers capable of self-activation and singlet oxygen production via a chemiluminescent reaction involving only a cancer marker and without requiring a light source. Cytotoxicity assays demonstrated the cytotoxic activity of all photosensitizers for prostate and breast tumor cell lines. Analysis of co-treatment effects revealed significant improvements for breast cancer, producing better results for all combinations than just for the individual photosensitizers and even Tamoxifen. By its turn, co-treatment for prostate cancer only presented better results for one combination than for just the isolated photosensitizers and Metformin. Nevertheless, it should be noted that the cytotoxicity of the isolated photosensitizers in prostate tumor cells was already very appreciable.

Abstract This paper reports the standard (p degrees = 0.1 MPa) molar enthalpies of formation, in the gaseous phase, at T = 298.15 K, of acridone and N-methylacridone as (50.0 +/- 5.0) kJ . mol(1) and (60.6 +/- 4.3) kJ . mol(1), respectively. These data were obtained from experimental thermodynamic parameters, namely the standard molar enthalpies of formation, in the crystalline phase, at T = 298.15 K, derived from the standard molar enthalpies of combustion measured by static-bomb combustion calorimetry, and the standard molar enthalpies of sublimation, at T = 298.15 K, determined by Calvet microcalorimetry or the Knudsen effusion techniques. Additionally, the gas-phase enthalpies of formation were estimated by G3(MP2)//B3LYP calculations, using several hypothetical gas-phase reactions, and were compared with the corresponding ones determined experimentally. The gas-phase keto-enol tautomerization chemical equilibrium of acridone M 9-acridinol was analysed using the Boltzmann's distribution, being confirmed that the equilibrium favours the formation of the keto form. The bond dissociation enthalpies (N-H) and (C-H) and the gas-phase acidities were also determined. The electrostatic potential surfaces and the frontier molecular orbitals were determined for both compounds, allowing us to infer about their reactivity properties. Other properties studied include the HOMO-LUMO energy gap and the ionization potential. (C) 2017 Elsevier Ltd.

Abstract Coelenterazine is a widespread bioluminescent substrate for a diverse set of marine species. Moreover, its imidazopyrazinone core is present in eight phyla of bioluminescent organisms. Given their very attractive intrinsic properties, these bioluminescent systems have been used in bioimaging, photodynamic therapy of cancer, as gene reporter and in sensing applications, among others. While it is known that bioluminescence results from the thermolysis of high-energy dioxetanones, the mechanism and dioxetanone species responsible for the singlet chemiexcitation of Coelenterazine are not fully understood. The theoretical characterization of the reactions of model Coelenterazine dioxetanones showed that efficient chemiexcitation is caused by a neutral dioxetanone with limited electron and charge transfer, by accessing a region of the PES where ground and excited states are nearly-degenerated. This finding was supported by calculation of equilibrium constants, which showed that only neutral dioxetanone is present in conditions associated with bioluminescence. Moreover, while cationic amino acids easily protonate amide dioxetanone, anionic ones cannot deprotonate the neutral species. These results indicate that, contrary to existent theories, efficient chemiexcitation can occur with significant electron and/or charge transfer. In fact, these processes can be prejudicial to chemiexcitation, as anionic dioxetanones showed a less efficient chemiexcitation despite the occurrence of significant electron and charge transfer.

Abstract In this study, a theoretical approach was used to study the UV absorption of the UVB filter, 4- methylbenzylidene camphor. The main objective of this work was to design new UVA filters based on this rather photo- stable compound, so that photo- degradation in this UV region can be avoided without the use of other molecules. This objective was achieved by the simultaneous addition of two appropriate substituents, which led to red- shifts of up to 0.69 eV while maintaining appreciable oscillator strength. Also, useful structure- energy relationships were derived, which allow for the development of more UVA filters based on 4- methylbenzylidene camphor.

Abstract Species with three-membered rings and the amide linkage are well studied. A quick perusal of the literature with SciFinder finds some 50 000 references to cyclopropanes and almost 300 000 references to amides. In the current paper, we discuss the structure and energetics of two understudied three-membered ring amides, 1,2-oxaziridine-3-one (5) (simultaneously describable as the simplest cyclic carbamate and simplest hydroxamate) and aziridine-2,3-dione (7) (simultaneously describable as the simplest imide and simplest alpha-ketoamide), with but 5 and nearly 10 references, respectively, for these two classes of compounds. Neither 1,2-oxaziridine-3-one (5) nor aziridine-2,3-dione (7), nor any derivative thereof, has been isolated. Calculational theory ameliorates the paucity of experimental information. The current study reports our computational findings for these and related species (e.g., enols and imidols) where we have used the G3(MP2)//B3LYP method.

Abstract 4-Methylbenzylidene camphor (4MBC) is an organic UV filter commonly used in sunscreens and many personal care products due to its ability to protect human skin against UVB solar radiation. 4MBC can exist as a (E)- or (Z)-isomer due to an exocyclic carbon-carbon double bond. In sunscreen formulations the (E) isomer predominates but under light exposure isomerization occurs from (E) to (Z). In this study we have performed density functional theory calculations with the B3LYP hybrid functional and two basis sets: 6-31G(d) and 6-311G(d,p) to obtain the gas-phase molecular structure and energetics of the (E)- and (Z)-isomers of 4MBC. For comparison and validation purposes this study has been extended to the parent molecule: camphor. To obtain more accurate energy values we have also used the G3(MP2)//B3LYP method. The standard molar enthalpy of formation of 4MBC in the gas-phase, at T = 298.15 K, was derived from these calculations using appropriately chosen reactions.

Abstract In this study we have performed a density functional theory (DFT) study of the molecular structure and energetics of the enol and keto tautomers of UVA filter 4-tert-butyl-4'-methoxydibenzoylmethane (BMDBM) and for comparison and validation purposes a similar study has been carried out for the parent molecule: dibenzoylmethane (DBM). The molecular structure of the enol and keto tautomers were obtained at the B3LYP/6-311++G(d,p) level. The enol forms were found to have a strong intramolecular resonance assisted hydrogen bond that accounts for the greater energetic stability of the enol relative to the keto form. The aromatic character of the six-membered enol rings has been analyzed by calculation of Nucleus Independent Chemical Shifts (NICS). The standard molar enthalpy of formation in the gas phase of BMDBM was derived from appropriately chosen reactions.

Abstract The growing awareness of the harmful effects of ultraviolet (UV) solar radiation has increased the production and consumption of sunscreen products, which contain organic and inorganic molecules named UV filters that absorb, reflect, or scatter UV radiation, thus minimizing negative human health effects. 4-tert-Butyl-4'-methoxydibenzoylmethane (BMDBM) is one of the few organic UVA filters and the most commonly used. BMDBM exists in sunscreens in the end l form which absorbs strongly in the UVA range. However, under sunlight irradiation tautomerization occurs to the keto form, resulting in the loss of UV protection. In this study we have performed quantum chemical calculations to study the excited-state molecular structure and excitation spectra of the enol and keto tautomers of BMDBM. This knowledge is of the utmost importance as the starting point for studies aiming at the understanding of its activity when applied on human skin and also its fate once released into the aquatic environment. The efficiency of excitation transitions was rationalized based on the concept of molecular orbital superposition. The loss of UV protection was attributed to. the enol -> keto phototautomerism and subsequent photodegradation. Although this process is not energetically favorable in the singlet bright state, photodegradation is possible because of intersystem crossing to the first two triplet states.

Abstract The standard massic energy of combustion, in oxygen, of the crystalline 9-anthracenecarboxylic acid was measured, at T=298.15 K, by static-bomb combustion calorimetry, from which the standard molar enthalpy of formation, in the condensed phase, was calculated as Delta(f)H degrees(m)(cr) = -(267.3 +/- 3.4) kJ . mol(-1). The standard molar enthalpy of sublimation of this acid, at T=298.15K, Delta(g)(cr)H degrees(m) = (139.4 +/- 0.9) kJ . mol(-1), was determined from the temperature-vapour pressure dependence, obtained by the Knudsen mass-loss effusion method. From the data presented above, the standard molar enthalpy of formation, in the gaseous phase, at T = 298.15 K, was derived, Delta(f)H degrees(m)(g) = -(127.9 +/- 3.5) kJ . mol(-1). The experimental result is interpreted in terms of enthalpic increments, molecular structure and compared with structurally similar compounds.