Identification of 3-Aryl-1-benzotriazole-1-yl-acrylonitrile as a Microtubule-Targeting Agent (MTA) in Solid Tumors.

Recently, a compound derived from recent scientific advances named 34 has emerged as the focus of this research, the aim of which is to explore its potential impact on solid tumor cell lines. Using a combination of bioinformatics and biological assays, this study conducted an in-depth investigation of the effects of 34. The results of this study have substantial implications for cancer research and treatment. 34 has shown remarkable efficacy in inhibiting the growth of several cancer cell lines, including those representing prostate carcinoma (PC3) and cervical carcinoma (HeLa). The high sensitivity of these cells, indicated by low IC50 values, underscores its potential as a promising chemotherapeutic agent. In addition, 34 has revealed the ability to induce cell cycle arrest, particularly in the G2/M phase, a phenomenon with critical implications for tumor initiation and growth. By interfering with DNA replication in cancer cells, 34 has shown the capacity to trigger cell death, offering a new avenue for cancer treatment. In addition, computational analyses have identified key genes affected by 34 treatment, suggesting potential therapeutic targets. These genes are involved in critical biological processes, including cell cycle regulation, DNA replication and microtubule dynamics, all of which are central to cancer development and progression. In conclusion, this study highlights the different mechanisms of 34 that inhibit cancer cell growth and alter the cell cycle. These promising results suggest the potential for more effective and less toxic anticancer therapies. Further in vivo validation and exploration of combination therapies are critical to improve cancer treatment outcomes.

Novel acrylonitrile derived imidazo[4,5-b]pyridines as antioxidants and potent antiproliferative agents for pancreatic adenocarcinoma.

We present the design, synthesis, computational analysis, and biological assessment of several acrylonitrile derived imidazo[4,5-b]pyridines, which were evaluated for their anticancer and antioxidant properties. Our aim was to explore how the number of hydroxy groups and the nature of nitrogen substituents influence their biological activity. The prepared derivatives exhibited robust and selective antiproliferative effects against several pancreatic adenocarcinoma cells, most markedly targeting Capan-1 cells (IC50 1.2-5.3 µM), while their selectivity was probed relative to normal PBMC cells. Notably, compound 55, featuring dihydroxy and bromo substituents, emerged as a promising lead molecule. It displayed the most prominent antiproliferative activity without any adverse impact on the viability of normal cells. Furthermore, the majority of studied derivatives also exhibited significant antioxidative activity within the FRAP assay, even surpassing the reference molecule BHT. Computational analysis rationalized the results by highlighting the dominance of the electron ionization for the antioxidant features with the trend in the computed ionization energies well matching the observed activities. Still, in trihydroxy derivatives, their ability to release hydrogen atoms and form a stable O-H⋯O•⋯H-O fragment upon the H• abstraction prevails, promoting them as excellent antioxidants in DPPH• assays as well.

Biological activity and computational analysis of novel acrylonitrile derived benzazoles as potent antiproliferative agents for pancreatic adenocarcinoma with antioxidative properties.

Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 µM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.

A systemic study of cyenopyrafen in strawberry cultivation system: Efficacy, residue behavior, and impact on honeybees (Apis mellifera L.).

The pesticide application method is one of the important factors affecting its effectiveness and residues, and the risk of pesticides to non-target organisms. To elucidate the effect of application methods on the efficacy and residue of cyenopyrafen, and the toxic effects on pollinators honeybees in strawberry cultivation, the efficacy and residual behavior of cyenopyrafen were investigated using foliar spray and backward leaf spray in field trials. The results showed that the initial deposition of cyenopyrafen using backward leaf spray on target leaves reached 5.06-9.81 mg/kg at the dose of 67.5-101.25 g a.i./ha, which was higher than that using foliar spray (2.62-3.71 mg/kg). The half-lives of cyenopyrafen in leaves for foliar and backward leaf spray was 2.3-3.3 and 5.3-5.9 d, respectively. The residues (10 d) of cyenopyrafen in leaves after backward leaf spray was 1.41-3.02 mg/kg, which was higher than that after foliar spraying (0.25-0.37 mg/kg). It is the main reason for the better efficacy after backward leaf spray. However, the residues (10 d) in strawberry after backward leaf spray and foliar spray was 0.04-0.10 and < 0.01 mg/kg, which were well below the established maximum residue levels of cyenopyrafen in Japan and South Korea for food safety. To further investigate the effects of cyenopyrafen residues after backward leaf spray application on pollinator honeybees, sublethal effects of cyenopyrafen on honeybees were studied. The results indicated a significant inhibition in the detoxification metabolic enzymes of honeybees under continuous exposure of cyenopyrafen (0.54 and 5.4 mg/L) over 8 d. The cyenopyrafen exposure also alters the composition of honeybee gut microbiota, such as increasing the relative abundance of Rhizobiales and decreasing the relative abundance of Acetobacterales. The comprehensive data on cyenopyrafen provide basic theoretical for environmental and ecological risk assessment, while backward leaf spray proved to be effective and safe for strawberry cultivation.

Estudo da atividade biológica de adutos Morita-Baylis-Hillman sobre Trypanosoma cruzi / Study of the biological activity of Morita-Baylis-Hillman adducts against Trypanosoma cruzi

A doença de Chagas, causada pelo protozoário hemoflagelado Trypanosoma cruzi, consiste em um grave problema de saúde pública na América Latina, com cerca de 7 a 8 milhões de pessoas infectadas. O benznidazol é atualmente o único fármaco disponível para o tratamento, apresentando boa atividade na fase aguda, mas com eficácia questionada na fase crônica, além de apresentar severos efeitos colaterais e longo período de tratamento. Tendo em vista a sua fácil síntese e baixo custo, adutos aromáticos oriundos da reação Morita-Baylis-Hillman têm sido considerados promissores como quimioterápicos. Neste sentido, foi avaliada a atividade tripanocida e citotóxica de seis adutos Morita-Baylis-Hillman. Para analisar possíveis efeitos dos adutos sobre estruturas específicas do protozoário foi utilizado a microscopia confocal a laser, através da marcação com Rodamina 123, MitoSOXT, Laranja de Acridina e Kit Live/Dead(R). As alterações morfológicas em parasitas submetidos ao tratamento foram acompanhadas por microscopia eletrônica de transmissão. Nossos resultados mostraram que todos os compostos foram capazes de inibir o crescimento de formas epimastigotas e causaram uma diminuição da viabilidade em formas tripomastigotas, apresentando uma moderada citotoxicidade para células de mamíferos. Os adutos MBH1, MBH2, MBH5 e MBH7 também foram efetivos em inibir a infecção de macrófagos e diminuir a viabilidade das formas amastigotas. Os compostos não foram capazes de alterar os níveis de produção do óxido nítrico em macrófagos. Análises pela microscopia confocal e microscopia eletrônica de transmissão (MET) apontam a mitocôndria como principal alvo intracelular destes compostos. Alterações compatíveis com a perda da viabilidade e morte celular por necrose e autofagia foram observadas por MET. Os resultados obtidos neste trabalho colocam os adutos Morita -Baylis-Hillman em evidência como agentes promissores para o tratamento da tripanossomíase americana.

Avaliação da atividade biológica de adutos derivados da reação morita-baylis-hillman sobre Trypanosoma cruzi: uma abordagem molecular, citoquímica e ultraestrutural / Biological activity evaluation of morita-baylis-hillman adducts against Trypanosoma cruzi: a molecular, cytochemical and ultrastructural approach

A doença de Chagas, causada pelo protozoário Trypanosoma cruzi, é um importante problema de saúde pública na América Latina, com cerca de 7,6 milhões de pessoas infectadas. O benznidazol e o nifurtimox são os únicos fármacos disponíveis para o tratamento, e além de apresentarem sérios efeitos colaterais, a sua eficácia na fase crônica da doença ainda é controversa. Neste sentido, nós sintetizamos o aduto Morita-Baylis-Hillman 3-hidroxi-2-metileno-3-(4-nitrofenilpropanonitrilo) (MBHA 3) e avaliamos sua atividade biológica sobre o T. cruzi. O MBHA 3 inibiu fortemente o crescimento das formas epimastigotas, com IC(50) / 72h de 28,5 µM e causou intensa lise de tripomastigotas, com IC(50)/ 24h de 25,5 µM. A análise ultraestrutural mostrou alterações morfológicas significantes, como arredondamento do corpo celular e desorganização intracelular. Alterações indicativas de apoptose, autofagia ou necrose também foram observadas nas células mais afetadas. A fim de melhor compreender o mecanismo envolvido na morte celular induzida pelo composto, nós utilizamos a microscopia confocal e a citometria de fluxo aliadas a sondas fluorescentes, como anexina-V (AV)/ iodeto de propídio (IP); Calceína-AM (CA)/ homodímero de etídio (HE); laranja de acridina (LA) e rodamina 123. O tratamento com 6 e 12 µg/ mL revelou uma alta porcentagem de células viáveis pela CA/ HE, mas também induziu alterações mitocondriais e aumento da marcação com a LA, sugerindo que um processo de morte celular programada (MCP) por autofagia poderia estar ocorrendo. Por outro lado, o tratamento com 24 µg/ mL levou à perda de viabilidade celular com danos excessivos sobre a membrana plasmática e mitocondrial e fragmentação inespecífica do DNA. Em conclusão, nossos achados sugerem que o MBHA 3, em alta concentração, induz MCP por necrose em T. cruzi.