Acute toxicity and antitumor potential of 1,3,4-trisubstituted-1,2,3-triazole dhmtAc-loaded liposomes on a triple-negative breast cancer model.

For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.

ENDOSCOPIC SUBMUCOSAL DISSECTION WITH CIRCUMFERENTIAL INCISION VERSUS TUNNELING METHOD FOR TREATMENT OF SUPERFICIAL ESOPHAGEAL CANCER.

BACKGROUND: Endoscopic submucosal dissection (ESD) of esophageal superficial neoplasm is associated with a high en bloc R0 resection rate and low recurrence. OBJECTIVE: We aim to compare the performance and clinical outcomes of ESD via ESD after circumferential incision (ESD-C) versus submucosal tunneling (ESD-T). METHODS: Single-center retrospective analysis of all consecutive patients who underwent ESD for superficial esophageal cancer, between 2009 and 2018. ESD-T was defined as the technique of making the mucosal incisions followed by submucosal tunneling in the oral to anal direction. ESD-C consisted of completing a circumferential incision followed by ESD. Main study outcomes included en bloc and R0 resection rates. Secondary outcomes included procedural characteristics, curative resection rate, local recurrence and adverse events. RESULTS: A total of 65 procedures (23 ESD-T and 42 ESD-C) were performed for ESCC (40; 61.5%) and BE-neoplasia (25; 38.5%). There were no statistically significant differences between patients who underwent ESD-T versus ESD-C in en bloc (91.3% vs 100%, P=0.12), R0 (65.2% vs 78.6%, P=0.24), curative resection rates (65.2% vs 73.8%, P=0.47) and mean procedure time (118.7 min with vs 102.4 min, P=0.35). Adverse events for ESD-T and ESD-C were as follows: bleeding (0 versus 2.4%; P=0.53), perforation (4.3% vs 0; P=0.61), esophageal stricture (8.7% versus 9.5%; P=0.31). Local recurrence was encountered in 8.7% after ESD-T and 2.4% after ESD-C (P=0.28) at a mean follow-up of 8 and 2.75 years, respectively (P=0.001). CONCLUSION: ESD-T and ESD-C appear to be equally effective with similar safety profiles for the management of superficial esophageal neoplasms.

Dissecção endoscópica submucosa com incisão circunferencial versus túnel submucoso no tratamento da neoplasia superficial do esôfago / Endoscopic submucosal dissection with circumferential incision versus tunneling method for treatment of superficial esophageal cancer

ABSTRACT BACKGROUND: Endoscopic submucosal dissection (ESD) of esophageal superficial neoplasm is associated with a high en bloc R0 resection rate and low recurrence. OBJECTIVE: We aim to compare the performance and clinical outcomes of ESD via ESD after circumferential incision (ESD-C) versus submucosal tunneling (ESD-T). METHODS: Single-center retrospective analysis of all consecutive patients who underwent ESD for superficial esophageal cancer, between 2009 and 2018. ESD-T was defined as the technique of making the mucosal incisions followed by submucosal tunneling in the oral to anal direction. ESD-C consisted of completing a circumferential incision followed by ESD. Main study outcomes included en bloc and R0 resection rates. Secondary outcomes included procedural characteristics, curative resection rate, local recurrence and adverse events. RESULTS: A total of 65 procedures (23 ESD-T and 42 ESD-C) were performed for ESCC (40; 61.5%) and BE-neoplasia (25; 38.5%). There were no statistically significant differences between patients who underwent ESD-T versus ESD-C in en bloc (91.3% vs 100%, P=0.12), R0 (65.2% vs 78.6%, P=0.24), curative resection rates (65.2% vs 73.8%, P=0.47) and mean procedure time (118.7 min with vs 102.4 min, P=0.35). Adverse events for ESD-T and ESD-C were as follows: bleeding (0 versus 2.4%; P=0.53), perforation (4.3% vs 0; P=0.61), esophageal stricture (8.7% versus 9.5%; P=0.31). Local recurrence was encountered in 8.7% after ESD-T and 2.4% after ESD-C (P=0.28) at a mean follow-up of 8 and 2.75 years, respectively (P=0.001). CONCLUSION: ESD-T and ESD-C appear to be equally effective with similar safety profiles for the management of superficial esophageal neoplasms.

RESUMO CONTEXTO: A dissecção endoscópica submucosa (DES) no tratamento da neoplasia superficial do esôfago está associada a uma alta taxa de ressecção R0 em bloco e baixa taxa de recorrência. OBJETIVO: O objetivo deste estudo é comparar o desempenho e os resultados clínicos da DES com incisão circunferencial (DES-C) versus com DES com túnel submucoso (DES-TS). MÉTODOS: Estudo retrospectivo de banco de dados coletados prospectivamente de um centro especializado em DES, investigando pacientes consecutivos submetidos à DES por câncer de esôfago superficial, entre 2009 e 2018. DES-TS foi definida como a técnica de realizar primeiro incisões na mucosa seguida de tunelamento submucoso no sentido oral para anal. DES-C consistiu em completar uma incisão circunferencial seguida da dissecção submucosa. As principais variáveis do estudo incluíram taxas de ressecção em bloco e R0. Os resultados secundários incluíram características do procedimento, taxa de ressecção curativa, recorrência local e eventos adversos. RESULTADOS: Um total de 65 procedimentos (23 DES-TS e 42 DES-C) foram realizados para CCE de esôfago (40; 61,5%) e neoplasia associada ao EB (25; 38,5%). Não houve diferenças estatisticamente significativas entre os pacientes submetidos a DES-TS versus DES-C nas taxas de ressecção em bloco (91,3% vs 100%, P=0,12), R0 (65,2% vs 78,6%, P=0,24), taxas de ressecção curativa (65,2% vs 73,8%, P=0,47) e tempo médio do procedimento (118,7 min com vs 102,4 min, P=0,35). Os eventos adversos para DES-TS e DES-C foram os seguintes: sangramento (0 vs 2,4%; P=0,53), perfuração (4,3% vs 0; P=0,61), estenose esofágica (8,7% vs 9,5%; P=0,31). A recorrência local foi encontrada em 8,7% após DES-TS e 2,4% após DES-C (P=0,28) em um seguimento médio de 8 e 2,75 anos, respectivamente (P=0,001). CONCLUSÃO: DES-TS e DES-C demostram ser igualmente eficazes com perfil de segurança semelhante para o tratamento das neoplasias superficiais do esôfago.

Ingestion of microplastic by ontogenetic phases of Stellifer brasiliensis (Perciformes, Sciaenidae) from the surf zone of tropical beaches.

Microplastics (<5 mm) are present in marine ecosystems worldwide where they can be ingested by a wide range of organisms from different trophic levels. In this study we analyzed the gastrointestinal tract of 443 specimens of Stellifer brasiliensis (124 juveniles, 254 subadults, and 65 adults) sampled in tropical beaches adjacent to the Paraíba River estuary. We found 1-3 microplastics in 42 fishes (9.48%), averaging 1.31 ± 0.52 microplastics per fish. The number of ingested microplastics by the different ontogenetic stages was statistically similar, but the adults had a higher ingestion frequency (13.8%). Among subadults, the condition factor of fishes that ingested microplastics was significantly smaller (p < 0.05) than those that had not ingested them. The ingestion of microplastics by the different ontogenetic stages of S. brasiliensis reflects the availability of this pollutant in the studied environment and highlights the vulnerability of fishes and other organisms through food webs.

Fishing marine debris in a northeast Brazilian beach: Composition, abundance and tidal changes.

This study aims to examine the composition and the spatial/tidal changes of marine debris caught with a fishing net during a fishery survey in two different areas of a sand beach at the northeast of Brazil. Samples were conducted weekly, at each moon phase, for two months using a beach seine net in the surf zone. Abundance of debris were estimate by swept area (items·km-1 and g·km-1). A total of 12 categories of debris were recorded. Plastic - both hard and soft types - was the most abundant debris category. Most fragments were classified as macro (20-100 mm) and mega debris (>100 mm). Significant differences (P < 0.05) between areas and tides were registered for plastic, metal and cloth. Spring tides were responsible for the high rates of marine debris found in the surf zone of Miramar beach. The results demonstrate the occurrence and abundance of litter in this fish nursery area and reinforce the need and importance of environmental protection and educational programs. CAPSULE ABSTRACT: Marine debris caught by a fishing net in the surf zone of Brazilian beach.

Composition, density and biomass of fish community from the surf zone as a function of the lunar cycle at Miramar Beach in Cabedelo, Paraíba

The influence of the moon cycles on the ichthyofauna has been little studied in the surf zone. In this study, the number of species, density and biomass were evaluated as a function of the moon. A total of 49 species distributed in 24 families were captured in two areas of Miramar beach. The mean density was significant high in the weaning and low in the new moon, while density and biomass together showed differences for areas. The most abundant species were Anchoa tricolor and Trachinotus falcatus (new moon), and Anchovia clupeoides showed significant differences in the waning moon. The RDA indicates that turbidity influenced significantly the presence of two species group. The group I were represented by Stellifer brasiliensis, Trachinotus goodei, A. clupeoides, Chilomycterus spinosus and Conodon nobilis that occurred on the waning and new phases in both areas, while the group II were represented by Polydactylus virginicus and Haemulopsis corvinaeformis in the full moon. The surf zones may also be strongly governed by the lunar phases. Therefore, the results found in this study, showed that the biological interactions between the species with turbidity and moon might explain the density and biomass variations for some species in the surf zone.(AU)

A influência das fases lunares sobre a ictiofauna tem sido pouco estudada na zona de arrebentação. Nesse estudo, foram avaliadas, o número de espécies, densidade e a biomassa da ictiofauna em função da lua. Foram capturadas 49 espécies distribuídas em 24 famílias em duas áreas na Praia de Miramar. A densidade foi significativamente elevada nas luas minguante e nova. Além disso, a densidade e biomassa juntas mostraram diferenças entre as áreas. As espécies mais abundantes na lua nova foram Anchoa tricolor e Trachinotus falcatus, e Anchovia clupeoides teve uma maior abundancia na lua minguante. O RDA, indicou que a turbidez influenciou significativamente a presença de dois grupos distintos. O grupo I, representado por Stellifer brasiliensis, Trachinotus goodei, A. clupeoides, Chilomycterus spinosus e Conodon nobilis estiveram presentes nas luas minguante e nova em ambas as áreas, e o grupo II, representado por Polydactylus virginicus e Haemulopsis corvinaeformis na lua cheia. As zonas de arrebentação também podem ser reguladas fortemente pelas fases lunares. Os resultados mostraram que as interações biológicas entre as espécies com a turbidez e as fases lunares podem explicar as variações de densidade e biomassa para algumas espécies na zona de arrebentação.(AU)

Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives.

In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 µM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents.

Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood)

BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6′-acetoxy-piliformic acid (2), 5′,6′-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells.

Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood).

BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6'-acetoxy-piliformic acid (2), 5',6'-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells.

In vitro leishmanicidal, antibacterial and antitumour potential of anhydrocochlioquinone A obtained from the fungus Cochliobolus sp.

The bioassay-guided fractionation of the ethyl acetate extract of the fungus Cochliobolus sp. highlighted leishmanicidal activity and allowed for anhydrocochlioquinone A (ANDC-A) isolation. MS, 1D and 2D NMR spectra of this compound were in agreement with those published in the literature. ANDC-A exhibited leishmanicidal activity with EC 50 value of 22.4 microgram/mL (44 mu M) and, when submitted to the microdilution assay against Gram-ositive and Gram-negative bacteria, showed a minimal inhibitory concentration against Staphylococcus aureus ATCC 25295 of 128 microgram/mL (248.7 mu M). It was also active against five human cancer cell lines, showing IC50 values from 5.4 to 20.3 mu M. ANDC-A demonstrated a differential selectivity for HL-60 (SI 5.5) and THP-1 (SI 4.3) cell lines in comparison with Vero cells and was more selective than cisplatin and doxorubicin against MCF-7 cell line in comparison with human peripheral blood mononuclear cells. ANDC-A was able to eradicate clonogenic tumour cells at concentrations of 20 and 50 mu M and induced apoptosis in all tumour cell lines at 20 mu M. These results suggest that ANDC-A might be used as a biochemical tool in the study of tumour cells biochemistry as well as an anticancer agent with durable effects on tumours.

Design, synthesis and structure-activity relationship studies of a novel focused library of 2,3,4-substituted oxazolidines with antiproliferative activity against cancer cell lines.

In the present work we describe the synthesis and antiproliferative evaluation of a focused library of 30 novel oxazolidines designed by modification of N-substituent, by ring variation, by alkyl variation or by extension of the structure. It was noted that carbamate and N,O-aminal groups were essential for activity. In general, replacement of the phenyl ring with pyridinyl was not tolerated. However, the introduction of a second phenyl ring with an appropriate spacer at the 3- or 4-position of the first phenyl ring generally enhanced the cytotoxic profile. Among all the prepared compounds, 24 was the most potent compound found in this class, being active on four of five cancer cell lines and it was 5-fold and 10-fold more potent than the lead compounds against HL60 and JURKAT cells, respectively. In addition, it showed relevant activity against MCF-7 and HCT-116 cells, which were resistant to lead. Moreover, 24 showed little antiproliferative activity against VERO, indicating low toxicity to normal cells. Thus, this compound has the potential to be developed as an anticancer agent.

Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells.

Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh). Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4). The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts. Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.

Metal complexes of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone: cytotoxic activity and investigation on the mode of action of the gold(III) complex.

Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

ABSTRACT The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC50 = 43-76 µM) and low cytotoxicity against Vero cells (IC50 > 100 M). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.

RESUMO O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI50=43-76 µM), com baixa citotoxicidade contra células Vero (CI50 > 100 M). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.

Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro.

Human cryptococcosis can occur as a primary or opportunistic infection and develop as an acute, subacute, or chronic, systemic infection involving different host organs. We evaluated the antifungal activity of thirteen compounds against Cryptococcus gattii and Cryptococcus neoformans in vitro, by assessing the toxicity of the compounds showing the greatest antifungal activity in VERO cells and murine macrophages. From these results, four compounds were considered promising for further studies because they displayed low cytotoxicity and significant antifungal activity. The heterocyclic compounds 1b, 1c, 1d, and 1m have antifungal activity levels between that of amphotericin B and fluconazole in vitro. The death curve of Cryptococcus spp. treated with these four compounds was similar to the curve obtained for amphotericin B, in that we observed a significant reduction in cell viability within the first 24 h of treatment. Additionally, we found that there was no effect when these compounds were combined with amphotericin and fluconazole, except for 1c, which antagonized the effect of amphotericin B against C. gattii, also reflected in the reduction of the post-antifungal effect (PAFE); however, this interaction did not alter the ergosterol content. The results shown in this paper reveal the discovery of novel thiazole compounds, which are easy to synthesize, and with potentially exhibit antifungal activity, and display low cytotoxicity in normal mammalian cells. These compounds can be used as prototypes for the design of new antifungal drugs against C. gattii and C. neoformans.

Synthesis of nitroaromatic compounds as potential anticancer agents.

Twenty-seven nitrated and non-nitrated compounds have been synthesized and tested for their growth inhibitory activity on three human cancer cells lines. Fourteen compounds were able to inhibit more than 50% of the growth of at least one of the cancer cell lines and five compounds exhibited high antiproliferative activity on human cancer cell lines (IC50 < 8.5 µM). The cytotoxicity of the compounds on Vero cell line was established in vitro to evaluate the selectivity. All active compounds have a good leaving group (bromide or chloride) at the benzylic position, indicating that the mechanism of action of these compounds is related to their alkylating properties. Two compounds (3 and 24) were selected for further studies in mice with Ehrlich solid tumors and display significant antitumor effects in vivo.

Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone: cytotoxicity and effect on the enzymatic activity of thioredoxin reductase and glutathione reductase.

Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone (H2Ac4oClPh) were assayed for their cytotoxicity against MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells. The thiosemicarbazone and most of the complexes were highly cytotoxic. H2Ac4oClPh and its gallium(III) and tin(IV) complexes did not show any inhibitory activity against thioredoxin reductase (TrxR) and glutathione reductase (GR). The palladium(II), platinum(II) and bismuth(III) complexes inhibited TrxR at micromolar concentrations but not GR. The antimony(III) and gold(III) complexes strongly inhibited TrxR at submicromolar doses with GR inhibition at higher concentrations. The selectivity of these complexes for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. TrxR inhibition is likely a contributing factor to the mode of action of the gold and antimony derivatives.