Daniela de Luna Martins

Novel properties of melanins include promotion of DNA strand breaks, impairment of repair, and reduced ability to damage DNA after quenching of singlet oxygen

Melanins have been associated with the development of melanoma and its resistance to photodynamic therapy (PDT). Singlet molecular oxygen ((1)O(2)), which is produced by ultraviolet A solar radiation and the PDT system, is also involved. Here, we investigated the effects that these factors have on DNA damage and repair. Our results show that both types of melanin (eumelanin and pheomelanin) lead to DNA breakage in the absence of light irradiation and that eumelanin is more harmful than pheomelanin. Interestingly, melanins were found to bind to the minor grooves of DNA, guaranteeing close proximity to DNA and potentially causing the observed high levels of strand breaks. We also show that the interaction of melanins with DNA can impair the access of repair enzymes to lesions, contributing to the perpetuation of DNA damage. Moreover, we found that after melanins interact with (1)O(2), they exhibit a lower ability to induce DNA breakage; we propose that these effects are due to modifications of their structure. Together, our data highlight the different modes of action of the two types of melanin. Our results may have profound implications for cellular redox homeostasis, under conditions of induced melanin synthesis and irradiation with solar light. These results may also be applied to the development of protocols to sensitize melanoma cells to PDT.

Synthesis, characterization and biological activities of 3-aryl-1,4-naphthoquinones – green palladium-catalysed Suzuki cross coupling

Quinones are important scaffolds that are present in a variety of natural products or synthetic bioactive molecules. Arylation is an important strategy for accomplishing structural modifications, leading to new potential candidates for use as drugs. In the present work, palladium-catalysed, ligandless and phosphine-free Suzuki coupling reactions between 2-hydroxy-3-iodo-1,4-naphthoquinone and boronic acids were employed to prepare several 2-hydroxy-3-aryl-1,4-naphthoquinones in aqueous conditions using microwave irradiation or conventional heating. Because of the biological activities of quinones, which are related to their ability to accept electrons to form semiquinones and hydroquinones, the electrochemical behaviour of the synthesized molecules was investigated. The Osiris and Molinspiration Cheminformatics programs, utilizing in silico analyses, imply that these naphthoquinones are candidates for use as drugs which was reinforced by the outcomes of the in vitro antifungal and trypanocidal activity tests. Our in vitro data indicated a MIC value of 8 μg mL−1 against Candida albicans ATCC 24433 strains, and an EC50 of 0.67 μM with respect to trypanocidal activity against Trypanosoma cruzi epimastigote strains (Y).

Investigation of cobalt(III)–TPA complexes as potential bioreductively activated carriers for naphthoquinone-based drugs

Four cobalt(III)–TPA complexes with 2-hydroxy-3-X-1,4-naphthoquinones (HNQ-X), X = methyl (1), chlorine (2), bromine (3) and iodine (4), were designed and investigated as potential bioreductively activated carriers for naphthoquinone-based drugs. The substituents X were used in order to avoid dimerization of the naphthoquinone ligands and evaluate their effect on the Co3+/Co2+ potential. The expected [Co(TPA)(NQ-X)]2+ species was obtained for the NQ-CH3 ligand in 1, while the chlorine, bromine and iodine derivatives fostered the attachment of a methoxide to the C(1)carbonyl atom to produce complexes 2, 3 and 4, respectively. The structure and electronic properties of the complexes were investigated by single crystal X-ray diffraction analysis and DFT calculations. Cyclic voltammetry analysis showed that the Co3+/Co2+ potential is 0.21 V for complex 1 and 0.32 V vs. SHE for complexes 2–4. Redox activation with dissociation of the naphthoquinones was successfully achieved by reduction of the complexes with the biologically relevant reducing agent ascorbic acid.

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)‐(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine‐phosphorylation‐regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.

Carboxylic acid chlorides as arylating agents in the palladium-catalyzed Heck reaction - The Blaser reaction

Heck reaction is a powerful tool in organic synthesis to perform C-C couplings by which functionalized alkenes can be obtained under mild conditions and great selectivity. Developing alternative methodologies where arylating agents different from the conventional aryl halides or triflates can be introduced with success is one of the areas of research nowadays. By these methodologies it is envisaged to provide better conditions for the industrial application of the palladium-catalyzed Heck C-C coupling. One of the aims of this research is to introduce non expensive arylating agents as well as to minimize waste. In this regard we describe in this paper some studies present in the literature where acid chlorides and other arylcarboxylic acid derivatives are employed as arylating agents in the Heck reactions.