Brenno A. D. Neto

Recent Developments in the Chemistry of Deoxyribonucleic Acid (DNA) Intercalators: Principles, Design, Synthesis, Applications and Trends

In the present overview, we describe the bases of intercalation of small molecules (cationic and polar neutral compounds) in DNA. We briefly describe the importance of DNA structure and principles of intercalation. Selected syntheses, possibilities and applications are shown to exemplify the importance, drawbacks and challenges in this pertinent, new, and exciting research area. Additionally, some clinical applications (molecular processes, cancer therapy and others) and trends are described.

Benzothiadiazole Derivatives as Fluorescence Imaging Probes: Beyond Classical Scaffolds.

This Account describes the origins, features, importance, and trends of the use of fluorescent small-molecule 2,1,3-benzothiadiazole (BTD) derivatives as a new class of bioprobes applied to bioimaging analyses of several (live and fixed) cell types. BTDs have been successfully used as probes for a plethora of biological analyses for only a few years, and the impressive responses obtained by using this important class of heterocycle are fostering the development of new fluorescent BTDs and expanding the biological applications of such derivatives. The first use of a fluorescent small-molecule BTD derivative as a selective cellular probe dates back to 2010, and since then impressive advances have been described by us and others. The well-known limitations of classical scaffolds urged the development of new classes of bioprobes. Although great developments have been achieved by using classical scaffolds such as coumarins, BODIPYs, fluoresceins, rhodamines, cyanines, and phenoxazines, there is still much to be done, and BTDs aim to succeed where these dyes have shown their limitations. Important organelles and cell components such as nuclear DNA, mitochondria, lipid droplets, and others have already been successfully labeled by fluorescent small-molecule BTD derivatives. New technological systems that use BTDs as the fluorophores for bioimaging experiments have been described in recent scientific literature. The successful application of BTDs as selective bioprobes has led some groups to explore their potential for use in studying membrane pores or tumor cells under hypoxic conditions. Finally, BTDs have also been used as fluorescent tags to investigate the action mechanism of some antitumor compounds. The attractive photophysical data typically observed for π-extended BTD derivatives is fostering interest in the use of this new class of bioprobes. Large Stokes shifts, large molar extinction coefficients, high quantum yields, high stability when stored in solution or as pure solids, no fading even after long periods of irradiation, bright emissions with no blinking, good signal-to-noise ratios, efficiency to transpose the cell membrane, and irradiation preferentially in the visible-light region are just some features noted by using BTDs. As the pioneering group in the use of fluorescent small-molecule BTDs for bioimaging purposes, we feel pleased to share our experience, results, advances, and personal perspectives with the readers of this Account. The readers will clearly note the huge advantages of using fluorescent BTDs over classical scaffolds, and hopefully they will be inspired and motivated to further BTD technology in the fields of molecular and cellular biology.

Ionic Liquid Supported Acid/Base-Catalyzed Production of Biodiesel

The transesterification (alcoholysis) reaction was successfully applied to synthesize biodiesel from vegetable oils using imidazolium-based ionic liquids under multiphase acidic and basic conditions. Under basic conditions, the combination of the ionic liquid 1-n-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (BMINTf2), alcohols, and K2CO3 (40 mol %) results in the production of biodiesel from soybean oil in high yields (>98%) and purity. H2SO4 immobilized in BMINTf2 efficiently promotes the transesterification reaction of soybean oil and various primary and secondary alcohols. In this multiphase process the acid is almost completely retained in the ionic liquid phase, while the biodiesel forms a separate phase. The recovered ionic liquid containing the acid could be reused at least six times without any significant loss in the biodiesel yield or selectivity. In both catalytic processes (acid and base), the reactions proceed as typical multiphasic systems in which the formed biodiesel accumulates as the upper phase and the glycerol by-product is selectively captured by the alcohol-ionic liquid-acid/base phase. Classical ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborate and hexafluorophosphate are not stable under these acidic or basic conditions and decompose.

The Biginelli Reaction with an Imidazolium–Tagged Recyclable Iron Catalyst: Kinetics, Mechanism, and Antitumoral Activity

The present work describes the synthesis, characterization, and application of a new ion-tagged iron catalyst. The catalyst was employed in the Biginelli reaction with impressive performance. High yields have been achieved when the reaction was carried out in imidazolium-based ionic liquids (BMI⋅PF6, BMI⋅NTf2, and BMI⋅BF4), thus showing that the ionic-liquid effects play a role in the reaction. Moreover, the ion-tagged catalyst could be recovered and reused up to eight times without any noticeable loss in activity. Mechanistic studies performed by using high-resolution electrospray-ionization quadrupole-time-of-flight mass (HR-EI-QTOF) spectrometry and kinetic experiments indicate only one reaction pathway and rule out the other two possibilities under the development conditions. The theoretical calculations are in accordance with the proposed mechanism of action of the iron catalyst. Finally, the 37 dihydropyrimidinone derivatives, products of the Biginelli reaction, had their cytotoxicity evaluated in assays against MCF-7 cancer cell linages with encouraging results of some derivatives, which were virtually non-toxic against healthy cell linages (fibroblasts).

What do we know about multicomponent reactions? Mechanisms and trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs

The current manuscript describes the importance, mechanism propositions, evidence and controversies associated with multicomponent reactions (MCRs). The following multicomponent reactions are presented and critically evaluated: the Biginelli, Hantzsch, Mannich, Passerini and Ugi reactions. The aim of this review is to highlight what we already know about the mechanisms associated with these MCRs and the evidence supporting the proposed reaction pathways. Controversies and prospects are also discussed herein.

Mechanistic Studies on Lewis Acid Catalyzed Biginelli Reactions in Ionic Liquids: Evidence for the Reactive Intermediates and the Role of the Reagents

This paper describes the use of common Lewis acids supported in imidazolium-based ionic liquids as the catalysts to promote the Biginelli reaction. The ionic liquid effect and the reaction mechanism are discussed on the basis of nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), and theoretical calculations. Indeed, the results showed that the ionic medium plays a fundamental role in the synthesis of biologically active dihydropyrimidinones due to the stabilization of the charged intermediates proposed in the mechanism. When conducted in an ionic liquid as solvent, the reaction mechanism is more complex than in other Lewis acid catalyzed Biginelli reactions.

On the use of 2,1,3-benzothiadiazole derivatives as selective live cell fluorescence imaging probes

Newly designed 2,1,3-benzothiadiazole-containing fluorescent probes with four excited state intramolecular proton transfer (ESIPT) sites were successfully tested in live cell-imaging assays using a confluent monolayer of human stem-cells (tissue). All tested dyes were compared with the commercially available DAPI and gave far better results.

Selective mitochondrial staining with small fluorescent probes: importance, design, synthesis, challenges and trends for new markers

The present manuscript describes the importance of small mitochondrion-specific fluorescent markers to study mitochondrial dynamics and related processes. The importance of mitochondria, their dynamic cellular processes, the use of fluorescent selective probes, limitations of selected commercially available fluorescent systems and recent developments on the synthesis and applications of small fluorescent probes and trends are discussed.

Ionically Tagged Iron Complex‐Catalyzed Epoxidation of Olefins in Imidazolium‐Based Ionic Liquids

A new ionophilic ligand and a new ionically tagged imidazolium-based iron(III) complex were synthesized and applied in the air oxidation (also hydrogen peroxide) of alkenes in imidazolium-based ionic liquids. At least ten recycling reactions were performed. The epoxidized olefin was obtained in very good yields of 84-91 %. Some important mechanistic insights are also provided based on electrospray ionization quadrupole-time of flight mass spectrometry for the oxidation reaction. These results indicate that oxidations can take place by two different pathways, depending on the reaction condition: a radical or a concerted mechanism. These results contribute towards a better understanding of iron-catalyzed oxidation mechanisms.

Charge-tagged acetate ligands as mass spectrometry probes for metal complexes investigations: applications in Suzuki and Heck phosphine-free reactions.

An acetate anion bearing an imidazolium cation as its charge tag was reacted with M(OAc)(2) complexes (where M = Ni, Cu, and Pd; in situ reaction) to form members of a new class of charge-tagged metal complexes. The formation of these unprecedented precatalysts with potential for cross-coupling reactions was confirmed by electrospray ionization (and tandem) mass spectrometry. The catalytic performance of the palladium complex was tested in Heck and Suzuki cross-coupling reactions, often with superior activity and yields as compared with Pd(OAc)(2).