Cristian O. Salas

Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease.

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.

Synthesis and antiprotozoal activity of naphthofuranquinones and naphthothiophenequinones containing a fused thiazole ring

The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.

Synthesis, Biological Evaluation, and Molecular Simulation of Chalcones and Aurones as Selective MAO-B Inhibitors

A series of chalcones and aurones were synthesized and evaluated in vitro as monoamine oxidase inhibitors (MAOi). Our results show that aurones, which had not been previously reported as MAOi, are MAO‐B inhibitors. Thus, both families inhibited selectively the B isoform of MAO in the micromolar range, offering novel scaffolds for the design of new and potent MAO inhibitors. The main structural requirements for their activity were characterized with the aid of 3D‐QSAR and docking studies.

2-Phenylaminonaphthoquinones and related compounds: Synthesis, trypanocidal and cytotoxic activities

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.

Synthesis of new phosphorescent imidoyl-indazol and phosphine mixed ligand Cu(I) complexes – structural characterization and photophysical properties

Four mononuclear Cu(I) complexes were prepared, described as [Cu(N,N)2]PF6 (1) and [Cu(N,N)(P,P)]PF6 (2–4), where N,N is N-(1-(2H-indazol-2-yl)ethylidene)-2,6-diisopropylaniline and P,P are phosphine derived ancillary ligands (bis[2-(diphenylphosphino)phenyl]ether (POP), bis(diphenylphosphino)ethane (dppe) or 2 PPh3). These new species were characterized by NMR, FT-IR, elemental analyses, cyclic voltammetry, UV-Vis – emission spectroscopy, transient absorption spectroscopy and DFT calculations. In addition, complexes 1 and 2 were characterized by X-ray diffraction. The four complexes showed an MLCT absorption band between 400 and 450 nm, in addition to a weakly structured phosphorescence in a 4:1 ethanol:methanol glassy matrix at 77 K. Complexes 2–4 have emission profiles that resemble the phosphorescence of the protonated N,N ligand, suggesting a triplet LC character of the lowest lying excited state at 77 K. By contrast, a mixed MLCT/LC triplet emission is most likely responsible for the phosphorescence in complex 1. Weak ligand-centered emission is also detected in the solid state at room temperature but only in the case of complexes 2 and 4, suggesting thermally activated deactivation processes in the case of 1 and 3. Notably, the transient absorption spectroscopy of complexes 2–4 in CH2Cl2 solution confirms a strong contribution from a ligand-centered (LC) triplet excited state, pointing towards a mixed 3MLCT/3LC character of the transient species in solution at room temperature, undergoing a non-radiative deactivation in the μs time-scale. This behavior markedly differs from that observed for complex 1, whose short-lived 3MLCT excited state is followed by ultrafast transient absorption spectroscopy.

N-Heterocyclic carbene copper(I) complex-catalyzed synthesis of 2-aryl benzoxazoles and benzothiazoles

A new and efficient synthesis of 2-arylbenzoxazoles and benzothiazoles using a copper N-heterocyclic carbene complex is described. In a simple protocol a variety of 2-substituted benzoxazoles and benzothiazoles were obtained via intramolecular coupling cyclization of 2-haloanilides/2-halothioanilides in good to excellent yields.

Synthesis and Pharmacophore Modelling of 2,6,9-Trisubstituted Purine Derivatives and Their Potential Role as Apoptosis-Inducing Agents in Cancer Cell Lines

A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds.

Efficient Indium-Mediated Dehalogenation of Aromatics in Ionic Liquid Media

An efficient indium-mediated dehalogenation reaction of haloaromatics and haloheteroaromatics in ionic liquids has been studied. This method is simple and effective in the presence of [bmim]Br. Furthermore, this methodology is environmentally friendly compared with conventional ones.

The selective cytotoxicity elicited by phytochemical extract from Senecio graveolens (Asteraceae) on breast cancer cells is enhanced by hypoxia.

Breast cancer is the second cause of cancer‑related deaths in woman and the incidence of the disease has increased worldwide, in part due to improvements in early detection. Several drugs with anticancer effects have been extracted from plants in the last 20 years, many of which are particularly effective against breast cancer cells. In particular, we have become interested in the ethanolic extract from Senecio graveolens (synonym of S. nutans), a plant commonly called Chachacoma, in an effort to isolate compounds that could demonstrate cytotoxic effects on breast cancer cells. Senecio (Asteraceae) is the largest gender in Chile comprising approximatly 200 species. These herbs inhabit areas over 3,500 meters above the sea level in the Andes Mountains. S. graveolens is commonly used by local communities for its medicinal properties, particularly its capacity to ameliorate high-altitude-associated sickness. The cytotoxic effect of the alcoholic extract from S. graveolens, as well as its most abundant compound 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone, were tested in the breast cancer cell lines ZR-75-1, MCF-7 and MDA-MB‑231, and non-tumorigenic MCF-10F cells. We show that the phytochemical extract was able to induce cytotoxicity in cancer cells but not in MCF-10F. Importantly, this effect was enhanced under hypoxic conditions. However, 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone, the main compound, did not by itself show an effective anticarcinogenic activity in comparison to the whole extract. Interestingly, the cytotoxic effect of the phytochemical extract was dependent on the basal MnSOD protein expression. Thus, cytotoxicity was increased when MnSOD levels were low, but resistance was evident when protein levels were high. Additionally, the crude extract seems to trigger cell death by a variety of processes, including autophagy, apoptosis and necrosis, in MCF-7 cells. In summary, S. graveolens extract possess anticancer activity displaying a specific cytotoxic effect on cancer cells, thus serving as a potential source of phytochemical compounds for cancer treatment.

MULTI-INSTRUMENTAL IDENTIFICATION OF ORPIMENT IN ARCHAEOLOGICAL MORTUARY CONTEXTS

ABSTRACT This paper reports on an unknown yellowish mineral compound found in an archaeological context from Chorrillos cemetery (Calama, Chile) dating to the Early Formative period (800 - 200 B.C.). We used optic microscopy, SEM, EDX, 1 H- RMN, 13 C-RMN, and infrared (IR) and Raman spectroscopy to tease out the chemical and molecular composition of the sample. The microscopic images show amorphous yellowish granulates with heterogeneous chemical surfaces. 1 H- RMN and 13 C-RMN negative results show that the sample is free of organic matter. The SEM and EDX indicate the presence of arsenic and sulfur in the sample. The IR and Raman analyses suggest the presence of orpiment which is a toxic yellow arsenic sulfide mineral. Keywords: Pigments, Raman spectroscopy, SEM-EDX, Chorrillos, Northern Chile. e-mail: jpabloogalde@yahoo.es INTRODUCTION Instrumental analyses of pigment usage have a significant value to play in many disciplines, such as natural resources, prehistoric artistic expression, archaeology and art history. It is a useful tool to identify and characterize pigments, elemental chemical composition, toxicity, usage, etc. Microsampling and non-destructive techniques are also important variables to consider when dealing with cultural patrimony and unique objects while pursuing chemical characterization and analyses of ancient samples