In silico and In vitro Determination of Antiproliferative Activity of Series N-Pyrrolyl Hydrazide-Hydrazones and Evaluation of their Effects on Isolated Rat Mycrosomes and Hepatocytes

Article

作者: Momekov, Georgi ; Zlatkov, Alexander ; Mateev, Emilio ; Tzankova, Diana ; Tzankova, Virginia ; Kondeva-Burdina, Magdalena ; Angelov, Borislav ; Georgieva, Maya

Background:The significant increase of patients suffering from different types of cancer, guides scientists to take prompt measures in the development of novel and effective antiproliferative agents, where the intercalation of heterocyclic fragment in the designed molecules has proven to be a useful practice.Objective:The newly synthesized compounds were obtained from the corresponding 1,4-dicarbonyl derivative through multicomponent reactions to produce biologically active target molecules and assessed by in silico and in vitro assays for their possible antitumor activity.Methods:The pharmacological bioassay was conducted in the panel of human tumor cell lines (i) SKW-3 (ACC 53) – human T-cell leukemia and (ii) HL-60 (ACC 3) - human acute myeloid leukemia (AML). The statistical processing of MTT data included the paired Student’s t-test with p ≤ 0.05 set as significance level.Results:All evaluated structures displayed higher cytotoxic effect against the acute myeloid leukemia HL-60 with 11o and 11p as the most active compared to the activity against SKW-3 cell line. Throughout the cytotoxicity screening two molecules, 11l and 12o, displayed comparable chemosensitivity on both cell lines. The corresponding hepatotoxicity on isolated rat hepatocytes and microsomes was also established, identifying 11, 12 and 12a as the least toxic and 11x, 11d, 12x and 12d as the most toxic derivatives.Conclusion:As most promising compound is underlined ethyl 1-(2-(2-((1-acetyl-1H-indol-3-yl)methylene)hydrazinyl)-2-oxoethyl)-5-(4-bromophenyl)-2-methyl-1H-pyrrole-3-carboxylate (11l) demonstrating highest activity on both evaluated tumor cell lines, decreased hepatotoxicity on all evaluated parameters and docking score of -7.517 kcal/mol.

2020-08-28·Journal of Biomedical Optics3区 · 医学

Pharmacokinetic characterization of fluorocoxib D, a cyclooxygenase-2-targeted optical imaging agent for detection of cancer

3区 · 医学

ArticleOA

作者: Olin, Shelly ; Stokes, Jennifer E ; Hecht, Silke ; Cekanova, Maria ; Uddin, Md Jashim ; Martin-Jimenez, Tomas ; Ryan, Phillip ; Marnett, Lawrence J ; Pandey, Sony

SIGNIFICANCEFluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells.AIMWe evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo.APPROACHPharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1 mg / kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo.RESULTSNo evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8 ± 50.5 ng / ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7 ± 0.9 using Image J analysis.CONCLUSIONSOur results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.

2020-02-01·Acta Tropica

Partial inhibition of the tricarboxylic acid cycle in Taenia crassiceps cysticerci after the in vitro exposure to a benzimidazole derivative (RCB15)

Article

作者: Vinaud, Marina C ; Fraga, Carolina M ; Costa, Tatiane L ; Picanço, Guaraciara de A ; Hernández-Campos, Alicia ; Alves, Daniella Smm ; Castillo, Rafael ; Lima, Nayana F ; Ambrosio, Javier ; Junior, Ruy de S Lino

The benzimidazole derivative, 6-chloro-5-(2,3-dichlorophenoxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB15), has a similar mode of action and efficacy as albendazole, a commonly used anthelminthic drugs. The aim of this study was to evaluate its influence on the tricarboxylic acid cycle in Taenia crassiceps cysticerci. The parasites were cultured in supplemented RPMI medium containing albendazole sulfoxide (ABZSO) or RCB15, for 24 h. Then, frozen in liquid nitrogen for organic metabolites extraction. Samples were analyzed by high performance liquid chromatography and organic acids of the tricarboxylic acid cycle were detected. It was possible to observe changes in the concentrations of all acids involved in this metabolic pathway, with the exception of α-ketoglutarate, which was not detected in the control group neither in most of the treated groups. It indicates that the parasite presented a partial inhibition of the tricarboxylic acid cycle. The significant increase in the concentration of citrate, oxaloacetate and succinate in the RCB15 treated groups may indicate an activation of the fumarate reductase pathway, leading to metabolic distress. Therefore RCB15 may be considered an alternative for the treatment of tissue parasitic diseases, since it induced changes in the main metabolic pathway of the parasite.

100 项与 B-823-10 相关的药物交易

登录后查看更多信息