Publications

Abstract Cancer is still a challenging disease to treat, both in terms of harmful side effects and therapeutic efficiency of the available treatments. Herein, to develop new therapeutic molecules, we have investigated the anticancer activity of halogenated derivatives of different components of the bioluminescent system of marine Coelenterazine: Coelenterazine (Clz) itself, Coelenteramide (Clmd), and Coelenteramine (Clm). We have found that Clz derivatives possess variable anticancer activity toward gastric and lung cancer. Interestingly, we also found that both brominated Clmd (Br-Clmd) and Clm (Br-Clm) were the most potent anticancer compounds toward these cell lines, with this being the first report of the anticancer potential of these types of molecules. Interestingly, Br-Clm possessed some safety profile towards noncancer cells. Further evaluation revealed that the latter compound induced cell death via apoptosis, with evidence for crosstalk between intrinsic and extrinsic pathways. Finally, a thorough exploration of the chemical space of the studied Br-Clm helped identify the structural features responsible for its observed anticancer activity. In conclusion, a new type of compounds with anticancer activity toward gastric and lung cancer was reported and characterized, which showed interesting properties to be considered as a starting point for future optimizations towards obtaining suitable chemotherapeutic agents.

Abstract Chemi- and bioluminescence are remarkable light-emitting phenomena, in which thermal energy is converted into excitation energy due to a (bio)chemical reaction. Among a wide variety of chemi-/bioluminescent systems, one of the most well-known and studied systems is that of marine imidazopyrazinones, such as Coelenterazine and Cypridina luciferin. Due to the increasing usefulness of their chemi-/bioluminescent reactions in terms of imaging and sensing applications, among others, significant effort has been made over the years by researchers to develop new derivatives with enhanced properties. Herein, we report the synthesis and chemiluminescent characterization of a novel dibrominated Coelenterazine analog. This novel compound consistently showed superior luminescence, in terms of total light output and emission lifetime, to natural imidazopyrazinones and commercially available analogs in aprotic media, while being capable of yellow light emission. Finally, this new compound showed enhanced chemiluminescence in an aqueous solution when triggered by superoxide anion, showing potential to be used as a basis for optimized probes for reactive oxygen species. In conclusion, bromination of the imidazopyrazinone scaffold appears to be a suitable strategy for obtaining Coelenterazines with enhanced properties.

Abstract Increased oxidative stress (OS) and depletion of nigrostriatal dopamine (DA) are closely linked to the neuro-degeneration observed in Parkinson's Disease (PD). Caffeic acid (CA)-based antioxidants were developed, and their inhibitory activities towards monoamine oxidases (MAOs) and catechol O-methyltransferases (COMT) were screened. The results showed that the incorporation of an extra double bond maintained or even boosted the antioxidant properties of CA. alpha-CN derivatives displayed redox potentials (Ep) similar to CA (1) and inhibited hMAO-B with low mu M IC50 values. Moreover, catechol amides acted as MB-COMT inhibitors, showing IC50 values within the low mu M range. In general, CA derivatives presented safe cytotoxicity profiles at concentrations up to 10 mu M. The formation of reactive oxygen species (ROS) induced by CA derivatives may be underlying the cytotoxic effects observed at higher concentrations. Catechol amides 3-6, 8-11 at 10 mu M protected cells against oxidative damage. Compounds 3 and 8 were predicted to cross the blood-brain barrier (BBB) by passive diffu-sion. In summary, we report for the first time BBB-permeant CA-based multitarget lead compounds that may restore DAergic neurotransmission (dual hMAO-B/MB-COMT inhibition) and prevent oxidative damage. The data represents a groundbreaking advancement towards the discovery of the next generation of new drugs for PD.

Abstract The intramolecular chemiexcitation of high-energy peroxide intermediates, such as dioxetanones, is an essential step in different chemi- and bioluminescent reactions. Here, we employed the Time-Dependent Density Functional Theory (TD-DFT) methodology to evaluate if and how external stimuli tune the intramolecular chemiexcitation of model dioxetanones. More specifically, we evaluated whether the strategic placement of ionic species near a neutral dioxetanone model could tune its thermolysis and chemiexcitation profile. We found that these ionic species allow for the dark catalysis of the thermolysis reaction by reducing the activation barrier to values low enough to be compatible with efficient chemi- and bioluminescent reactions. Furthermore, while the inclusion of these species negatively affected the chemiexcitation profile compared with neutral dioxetanones, these profiles appear to be at least as efficient as anionic dioxetanones. Thus, our results demonstrated that the intramolecular chemiexcitation of neutral dioxetanones can be tuned by external stimuli in such a way that their activation barriers are decreased. Thus, these results could help to reconcile findings that neutral dioxetanones could be responsible for efficient chemi-/bioluminescence, while being typically associated with high activation parameters.

Abstract 2-(1,3-Benzothiazol-2-yl)-4H-chromen-4-one and spiro[1,4-benzothiazine-2,2'-chromene]-3,4'(3'H,4H)-dione have been synthesized from 4-oxo-4H-chromene-2-carboxylic acid. The course of the reaction that usually occurs between the activated carboxylic acid and aromatic amines was changed upon the use of different reaction conditions (acidic or basic) and 2-aminobenzenethiol. As a result, new heterocyclic derivatives were obtained. Structures of the compounds have been established on the basis of spectral (1D and 2D NMR spectra) and X-ray data.

Abstract The thermolysis of dioxetanones is a key process in the intramolecular chemiexcitation step of several chemi-and bioluminescent reactions. This step is generally explained with mechanisms based on either electron transfer (ET), such as the Chemically Initiated Electron-Exchange Luminescence (CIEEL) mechanism, or charge transfer (CT), such as the Charge Transfer-Initiated Luminescence (CTIL) mechanism. Here, we have used a TD-DFT approach to characterize the thermolysis and chemiexcitation steps of model dioxetanones, to rationalize the role of ET/CT in those intramolecular processes. Our results showed that ET/CT can reduce the activation barrier of the thermolysis reaction, by reducing the repulsion between the reacting fragments (ketone and CO2 moieties) that originate during peroxide bond breaking. However, in terms of singlet chemiexcitation profiles, those of non-CIEEL/CTIL-based dioxetanones appear to be more efficient than of CIEEL/CTIL-based ones. Furthermore, the ground state to singlet excited state transitions were found to be local excitations, without CT between the peroxide ring and the electron-rich moiety. So, ET/CT appear to be responsible for tuning the activation barrier of the thermolysis reaction, without playing a role in efficient singlet chemiexcitation itself.

Abstract Coelenterazine and other imidazopyrazinones are important bioluminescent substrates widespread in marine species and can be found in eight phyla of luminescent organisms. Light emission from these systems is caused by the formation and subsequent thermolysis of a dioxetanone intermediate, whose decomposition allows for efficient chemiexcitation to singlet excited states. Interestingly, some studies have also reported the involvement of unexpected dioxetane intermediates in the chemiand bioluminescent reactions of Coelenterazine, albeit with little information on the underlying mechanisms of these new species. Herein, we have employed a theoretical approach based on density functional theory to study for the first time the thermolysis reaction and chemiexcitation profile of two Coelenterazine dioxetanes. We have found that the thermolysis reactions of these species are feasible but with relevant energetic differences. More importantly, we found that the singlet chemiexcitation profiles of these dioxetanes are significantly less efficient than the corresponding dioxetanones. Furthermore, we identified triplet chemiexcitation pathways for the Coelenterazine dioxetanes. Given this, the chemiexcitation of these dioxetanes should lead only to minimal luminescence. Thus, our theoretical investigation of these systems indicates that the thermolysis of these dioxetanes should only provide dark pathways for the formation of nonluminescent degradation products of the chemi- and bioluminescent reactions of Coelenterazine and other imidazopyrazinones.

Abstract Pharmaceuticals are becoming increasingly more relevant water contaminants, with photocatalysts (such as TiO2) being a promising approach to remove these compounds from water. However, TiO2 has poor sunlight harvesting capacity, low photonic efficiency, and poor adsorption towards organic pollutants. One of the emerging strategies to enhance the photocatalytic performance of TiO2 is by conjugating it with fluorescent carbon dots. Herein, we performed a critical review of the development of TiO2 - carbon dots nanocomposites for the photocatalytic removal of pharmaceuticals. We found that carbon dots can improve the photocatalytic efficiency of the resulting nanocomposites, mostly due to increasing the adsorption of organic pollutants and enhancing the absorption in the visible range. However, while this approach shows significant promise, we also identified and discussed several aspects that need to be addressed before this strategy could be more widely used. We hope that this review can guide future studies aiming to the development of enhanced photocatalytic TiO2 - carbon dots nanocomposites.

Abstract Er3+/Yb3+ doped/co-doped NaGdF4 upconversion phosphor nanoparticles were synthesized via the thermal decomposition route of synthesis. The oc-phase crystal structure and nanostructure of these particles were confirmed using XRD and FE-SEM analysis. In the power-dependent upconversion analysis, different emission bands at 520 nm, 540 nm, and 655 nm were obtained. The sample was also examined for cathodoluminescence (CL) analysis at different filament currents of an electron beam. Through CL analysis, different emission bands of 526 nm, 550 nm, 664 nm, and 848 nm were obtained. The suitability of the present sample for temperature-sensing applications at a wide range of temperatures, from room temperature to 1173 K, was successfully demonstrated.