Richard Michael Grazul

Novel antitumor adamantane–azole gold(I) complexes as potential inhibitors of thioredoxin reductase

AbstractGold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane–1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum–mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand–enzyme complex prior the formation of covalent bond with gold center.Graphical abstractThe structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds.

Antitumor, antibiotic and antileishmanial properties of the Pyranonaphthoquinone Psychorubrin from Mitracarpus frigidus

The bioactivity guided fractionation of the dichloromethane extract of Mitracarpus frigidus afforded the pyranonaphthoquinone psychorubrin. This compound, hitherto unknown in the genus Mitracarpus, had its biological activity evaluated against one panel of bacteria and two fungi, three tumor cell lines (HL60, Jurkat and MCF-7) and four Leishmania species. Its identity was confirmed unambiguously by (1)H, (13)C, (1)H-COSY, IR and UV-Vis spectroscopy and mass spectrometry. Psychorubrin displayed a very promising antitumor with IC(50) of 4.5, 5.6 and 1.1 µM for HL60, Jurkat and MCF-7 cell lines, respectively. Antimicrobial activity, mainly against Cryptococcus neoformans (MIC of 87.3 µM) was observed. A pronounced antileishmanial potential was also verified with IC(50) varying from 1.7 to 2.7 µM for the Leishmania species tested. This is the first report of the presence of pyranonapthoquinones in the Mitracarpus genus, which may serve as a chemotaxonomical marker.

Synthesis, cytotoxicity and antileishmanial activity of some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines.

We report herein the condensation of 4,7‐dichloroquinoline (1) with tryptamine (2) and D‐tryptophan methyl ester (3). Hydrolysis of the methyl ester adduct (5) yielded the free acid (6). The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.

The effect of essential oil of Syzygium cumini on the development of granulomatous inflammation in mice

The anti-inflammatory and apoptotic activity of the essential oil of Syzygium cumini (L.) Skeels, Myrtaceae, leaves was investigated in vivo. The antiinflammatory action and chronic granulomatous inflammation in BALB/c mice, intravenously infected with Mycobacterium bovis, BCG, (Bacillo Calmet Guerim), was judged by measuring and classifying the granulomas formed in the hepatic parenchyma. The degree of apoptosis in the inflammatory cells was also measured. A reduction in the granulomatous area and a change in the pattern of the granulomas were found. Anti-mycobacterial activity of the essential oil against M. bovis was detected in vitro by an interferometric method in liquid culture medium. The chemical constituents of the essential oil were determined by GC/MS. Higher yields of the essential oil of S. cumini leaves were obtained by extraction in a Clevenger apparatus when the fresh leaves were previously frozen as a pre-processing step. The essential oil obtained from this plant demonstrated a statistically significant and dramatic effect in the chosen model system.

Colonization by Chironomidae Larvae in Decomposition Leaves of Eichhornia azurea in a Lentic System in Southeastern Brazil

Abstract The objective of this study was to analyze the colonization of Chironomidae (Diptera) larvae during the decomposition of Eichhornia azurea (Swartz) Kunth (Commelinales: Pontederiaceae) leaves in a lake in southeastern Brazil in two seasons of the year. The experiment was conducted from September to November 2007 and February to April 2008. In each period, 21 litter bags were used, each containing 10 g of dried leaves. Three bags were removed after 2, 5, 8, 12, 25, 45, and 65 days of colonization. The decomposition rate of the E. azurea leaves was rapid in both seasons, with no significant difference between them. The Chironomidae showed higher density than the other invertebrates. Goeldichironomus, Tonytarsus, and Corynoneura were the most abundant genera of Chironomidae. The invertebrate density increased during the experiment, differing within days but not between seasons. The faunal composition differed between the decomposition phases (initial and final), but did not differ between the seasons (dry and wet). The taxa Ablabesmyia, Caladomyia, Chironomus, Goeldichironomus, and Parachironomus were the most closely related to the final days of the experiment. Litter was the main food item found in the gut contents of the organisms of all the genera analyzed, both at the beginning and end of the decomposition. We believe that the feeding activity combined with the high larval density is an important factor contributing to the rapid decomposition of the E. azurea leaves. In conclusion, the succession process along the detritus chain of E. azurea was more important in structuring the assemblage of Chironomidae larvae than seasonal variations.

Platinum(II) and palladium(II) aryl-thiosemicarbazone complexes: synthesis, characterization, molecular modeling, cytotoxicity, and antimicrobial activity

Platinum(II) and palladium(II) complexes [ML2] have been isolated from reaction of K2PtCl4 or K2PdCl4 and ligands (L) derived from thiosemicarbazones. The complexes were characterized by elemental analysis, Raman, IR, and NMR spectroscopy. In addition, quantum mechanical calculations were used to predict their structures and spectroscopic properties. For the first time, theoretical calculations using 195Pt NMR data were used to support the suggested structures. The results indicate that the thionic sulfur and the azomethine nitrogen are bonded to the metal ion in a trans configuration. Antibacterial activities and cytotoxicities of the complexes to B16-F10 and CT26.WT cell lines were also investigated. Some of the complexes demonstrated superior cytotoxic activity compared to cisplatin. Graphical Abstract

Platinum(II) complexes containing long-chain hydrophobic N-alkyl-diamine ligands: Synthesis, characterization, molecular modeling, and cytotoxic activity

A series of novel platinum(II) complexes derived from N-alkyl-ethanediamine and N-alkyl-propanediamine ligands were prepared and characterized. These complexes contain a long chain aliphatic diamine where the carbon length is variable and present a hydroxyl group in two different positions. The complexes with the ethanediamine derivatives were prepared from K(2)PtCl(4). Interestingly, the propanediamine derivatives did not react well with this platinum salt under the experimental conditions normally employed and could only be obtained from the more reactive K(2)PtI(4). A theoretical molecular modeling study was performed to understand this difference in reactivity and it showed that the conformation around the diamine plays an important role in the ring closure step of complex formation. The complexes had their cytotoxicity investigated in B16F1, CT26, B16F10, and MDA cell lines. Some of them demonstrated superior activity when compared to cisplatin and carboplatin. We were also able to confirm a structure-activity relationship between cytotoxicity and carbon chain length.

Insights into the multi-equilibrium, superstructure system based on β-cyclodextrin and a highly water soluble guest.

Pentamidine isethionate (PNT) is an antiprotozoal active in many cases of leishmaniasis, despite the present limitations including high toxicity and parenteral administration. In the present work, a PNT encapsulation strategy into β-cyclodextrin cavity at 1:1 and 2:1 (βCD:PNT) molar ratios was used in order to improve the drugs physical and chemical properties. Combining thermodynamic and structural approaches such as isothermal titration calorimetry (ITC), electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance ((1)H NMR, and ROESY) the inclusion process and the thermodynamics parameters were identified. ITC and ESI-MS experimental data suggest the simultaneous formation of different supramolecular complexes in solution. Moreover, NMR data are in accordance with these results, suggesting a deep inclusion of PNT into the βCD cavity, through correlations observed in 2D ROESY contour maps. The systems were also characterized by FTIR, TG/DTA and SEM. These techniques indicate the formation of inclusion complex in the solid state. In vivo PNT activity was evaluated orally in mice. The inclusion complex showed a significant reduction of parasite load compared to free PNT.

1‐(7‐Chloro‐1,4‐dihydroquinolin‐4‐ylidene)thiosemicarbazide and its hydrochloride: evidence for the existence of a stable imine tautomer in the solid state of 4‐aminoquinoline free bases, an anomalous case in nitrogen heterocycles

In the solid state, crystals of both 1-(7-chloro-1,4-dihydroquinolin-4-ylidene)thiosemicarbazide-methanol-water (2/1/1), 2C10H9ClN4S·CH3OH·H2O, (I), and its hydrochloride salt {systematic name: [(7-chloro-1,4-dihydroquinolin-4-ylidene)azaniumyl]thiourea chloride}, C10H10ClN4S(+)·Cl(-), (II), assume the imine tautomeric form, contrary to other 4-amino-7-chloroquinolines. Of particular interest are the N-C bond lengths, which have appreciable double-bond character, and the C-N-C aromatic ring bond angle. Both of these parameters have been studied extensively in 4-amino-substituted quinolines. The crystal structures of (I) and (II) in this study provide interesting examples of the amino-imino tautomerism which exists in this class of compound and is, to the best of our knowledge, hitherto unreported.

Isolation, spectral characterization, molecular docking, and cytotoxic activity of alkaloids from Erythroxylum pungens O. E. Shulz

Stem bark, root bark, and leaf extracts of Erythroxylum pungens were subjected to phytochemical analysis. N,N-dimethyltryptamine (DMT) was isolated and characterized from E. pungens roots. This unprecedented result is remarkable since no indole alkaloid has been previously reported from Erythroxylaceae so far. Eleven known tropane alkaloids were identified by their mass spectra and 3-(2-methylbutyryloxy)tropan-6,7-diol as well as 3-(2-methylbutyryloxy)nortropan-6,7-diol were isolated and characterized based on mass spectrometry, 1H, 13C, COSY, and NOESY NMR analysis. The complete NMR data are reported for the first time. Inverse Structure-based and Ligand-Based virtual screening were carried out to identify possible targets for 3-(2-methylbutyryloxy)tropan-6,7-diol. The level of cytotoxicity of this tropane alkaloid aliphatic ester was discrete with potencies on the order of 0.3-1.0 mg/mL and better results against HeLa (50% cell viability reduction). Otherwise, atropine (0.3 mg/mL), a Solanaceae tropane alkaloid, and DMT (0.5 mg/mL) from E. pungens roots impaired at 50% the cell viability against HeLa, SiHa, PC3, and 786-0. This study stimulates scientific investigation of the impact of edaphoclimatic features in a semi-arid environment on tropane alkaloid biosynthesis.