Imidazoles and Oxazoles from Lapachones and Phenanthrene-9,10-dione: A Journey through their Synthesis, Biological Studies, and Optical Applications.

Diverse structural frameworks are found in natural compounds and are well known for their chemical and biological properties; such compounds include the imidazoles and oxazoles. Researchers worldwide are continually working on the development of methods for synthesizing new molecules bearing these basic moiety and evaluating their properties and applications. To expand the knowledge related to azoles, this review summarizes important examples of imidazole and oxazole derivatives from 1,2-dicarbonyl compounds, such as lapachones and phenanthrene-9,10-diones, not only regarding their synthesis and biological applications but also their photophysical properties and uses. The data concerning the latter are particularly scarce in the literature, which leads to underestimation of the potential applications that can be envisaged for these compounds.

Rhodium(III)-Catalyzed C-H/N-H Alkyne Annulation of Nonsymmetric 2-Aryl (Benz)imidazole Derivatives: Photophysical and Mechanistic Insights.

Rhodium(III) catalysis enabled C-H/N-H alkyne annulation of nonsymmetric imidazole derivatives. This study encompasses the synthesis of imidazoles from a naturally occurring quinoidal compound and their use for the preparation of rigid π-extended imidazole derivatives with outstanding fluorescence. Our study also brings to light the photophysical aspects and the mechanism of the reaction studied via computational calculations. This method provided an efficient and versatile tool for the synthesis of fluorescent compounds with a wide range of chemical and biological applications.

Natural product-inspired profluorophores for imaging NQO1 activity in tumour tissues.

Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging.

Quinone-based fluorophores for imaging biological processes.

Quinones are privileged chemical structures playing crucial roles as redox and alkylating agents in a wide range of processes in cells. The broad functional array of quinones has prompted the development of new chemical approaches, including C-H bond activation and asymmetric reactions, to generate probes for examining their activity by means of fluorescence imaging. This tutorial review covers recent advances in the design, synthesis and applications of quinone-based fluorescent agents for visualizing specific processes in multiple biological systems, from cells to tissues and complex organisms in vivo.

Controlled Release of Nor-ß-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-ß-lapachone (NßL) 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 NßL on PLGA. Finally, the cytotoxic activity of NßL against PC3M human prostate cancer cells was demonstrated to be significantly enhanced when delivered by PLGA microcapsules in comparison with the free drug.

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.

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.

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.

Aryl-Phenanthro[9,10-d]imidazole: A Versatile Scaffold for the Design of Optical-Based Sensors.

Fluorescent and colorimetric sensors are important tools for investigating the chemical compositions of different matrices, including foods, environmental samples, and water. The high sensitivity, low interference, and low detection limits of these sensors have inspired scientists to investigate this class of sensing molecules for ion and molecule detection. Several examples of fluorescent and colorimetric sensors have been described in the literature; this Review focuses particularly on phenanthro[9,10-d]imidazoles. Different strategies have been developed for obtaining phenanthro[9,10-d]imidazoles, which enable modification of their optical properties upon interaction with specific analytes. These sensing responses usually involve changes in the fluorescence intensity and/or color arising from processes like photoinduced electron transfer, intramolecular charge transfer, intramolecular proton transfer in the excited state, and Förster resonance energy transfer. In this Review, we categorized these sensors into two different groups: those bearing formyl groups and their derivatives and those based on other molecular groups. The different optical responses of phenanthro[9,10-d]imidazole-based sensors upon interaction with specific analytes are discussed.

Ruthenium-catalyzed C-H oxygenation of quinones by weak O-coordination for potent trypanocidal agents.

Ruthenium-catalysis enabled the C-5 selective C-H oxygenation of naphthoquinones, and also sets the stage for the site-selective introduction of a hydroxyl group into anthraquinones. A-ring modified naphthoquinoidal compounds represent an important class of bioactive quinones for which the present study encompasses the first C-H oxygenation strategy by weak O-coordination.

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.

Encapsulation of nor-ß-lapachone into poly(d,l)-lactide-co-glycolide (PLGA) microcapsules: full characterization, computational details and cytotoxic activity against human cancer cell lines.

In this work, we characterize nor-ß-lapachone-loaded (NßL-loaded) microcapsules prepared using an emulsification/solvent extraction technique. Features such as surface morphology, particle size distribution, zeta potential, optical absorption, Raman and Fourier transform infrared spectra, thermal analysis data, drug encapsulation efficiency, drug release kinetics and in vitro cytotoxicity were studied. Spherical microcapsules with a size of 1.03 ± 0.46 µm were produced with an encapsulation efficiency of approximately 19%. Quantum DFT calculations were also performed to estimate typical interaction energies between a single nor-ß-lapachone molecule and the surface of the microparticles. The NßL-loaded PLGA microcapsules exhibited a pronounced initial burst release. After the in vitro treatment with NßL-loaded microcapsules, a clear phagocytosis of the spheres was observed in a few minutes. The cytotoxic activity against a set of cancer cell lines was investigated.

Selective endocytic trafficking in live cells with fluorescent naphthoxazoles and their boron complexes.

Fluorescent naphthoxazoles and their boron derivatives have been synthesized and applied as superior and selective probes for endocytic pathway tracking in live cancer cells. The best fluorophores were compared with the commercially available acridine orange (co-staining experiments), showing far better selectivity.