Gleiston G. Dias

1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 μM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

1,3-Azoles from ortho-naphthoquinones: synthesis of aryl substituted imidazoles and oxazoles and their potent activity against Mycobacterium tuberculosis.

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 μg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.

Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8μM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6μM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

Controlled Release of Nor-β-lapachone by PLGA Microparticles: A Strategy for Improving Cytotoxicity against Prostate Cancer Cells.

Prostate cancer is one of the most common malignant tumors in males and it has become a major worldwide public health problem. This study characterizes the encapsulation of Nor-β-lapachone (NβL) in poly(d,l-lactide-co-glycolide) (PLGA) microcapsules and evaluates the cytotoxicity of the resulting drug-loaded system against metastatic prostate cancer cells. The microcapsules presented appropriate morphological features and the presence of drug molecules in the microcapsules was confirmed by different methods. Spherical microcapsules with a size range of 1.03 ± 0.46 μm were produced with an encapsulation efficiency of approximately 19%. Classical molecular dynamics calculations provided an estimate of the typical adsorption energies of NβL on PLGA. Finally, the cytotoxic activity of NβL against PC3M human prostate cancer cells was demonstrated to be significantly enhanced when delivered by PLGA microcapsules in comparison with the free drug.

Fluorescent oxazoles from quinones for bioimaging applications

This work describes a synthetic strategy for the syntheses of four new fluorescent excited state intramolecular proton transfer (ESIPT) prone oxazole derivatives synthesized from lapachol, a naturally occurring naphthoquinone isolated from the Tabebuia species (ipe tree). DFT calculations were performed to understand the ESIPT stabilizing process of these new derivatives. The new structures were designed to have improved lipophilic and balanced hydrophobic properties toward a selective cellular staining of lipid-based structures, that is, lipid inclusions in the cytosol. Cell-imaging experiments returned interesting results and showed the molecular architecture of the four derivatives had a great influence over the stabilizing processes in the excited state and over the selection of lipid inclusions inside the cells.

Quinone-Derived π-Extended Phenazines as New Fluorogenic Probes for Live-Cell Imaging of Lipid Droplets

We describe a new synthetic methodology for the preparation of fluorescent π-extended phenazines from the naturally-occurring naphthoquinone lapachol. These novel structures represent the first fluorogenic probes based on the phenazine scaffold for imaging of lipid droplets in live cells. Systematic characterization and analysis of the compounds in vitro and in cells led to the identification of key structural features responsible for the fluorescent behavior of quinone-derived π-extended phenazines. Furthermore, live-cell imaging experiments identified one compound (P1) as a marker for intracellular lipid droplets with minimal background and enhanced performance over the lipophilic tracker Nile Red.

A UBI 31-38 Peptide-Coumarin Conjugate: Photophysical Features, Imaging Tracking And Synergism With Amphotericin B Against Cryptococcus

Cryptococcosis is a fungal disease of global significance for which new effective treatments are needed. The conjugation of the synthetic antimicrobial peptide fragment UBI 31-38 to a coumarin derivative showed to be an effective approach for the design of a novel anticryptococcal agent. In addition to antifungal activity, the conjugate exhibited intense fluorescence, which could be valuable for mechanistic investigations of this molecule. In this work, we studied the photophysical properties of the conjugate and confocal scanning laser microscopy was used to inspect the distribution of the peptide-coumarin conjugate in Cryptococcus cell. The synergism of this compound with amphotericin B or fluconazole against C. gattii and C. neoformans strains was also investigated. The results indicated that the fluorescent conjugate alone as well as its combination with amphotericin B are promising tools against cryptococcosis.