Browsing by Author "Rossi A."

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    Benzimidazoles Containing Piperazine Skeleton at C-2 Position as Promising Tubulin Modulators with Anthelmintic and Antineoplastic Activity
    (2023-11-01) Anichina K.; Mavrova A.; Vuchev D.; Popova-Daskalova G.; Bassi G.; Rossi A.; Montesi M.; Panseri S.; Fratev F.; Naydenova E.
    Benzimidazole anthelmintic drugs hold promise for repurposing as cancer treatments due to their interference with tubulin polymerization and depolymerization, manifesting anticancer properties. We explored the potential of benzimidazole compounds with a piperazine fragment at C-2 as tubulin-targeting agents. In particular, we assessed their anthelmintic activity against isolated Trichinella spiralis muscle larvae and their effects on glioblastoma (U-87 MG) and breast cancer (MDA-MB-231) cell lines. Compound 7c demonstrated exceptional anthelmintic efficacy, achieving a 92.7% reduction in parasite activity at 100 μg/mL after 48 hours. In vitro cytotoxicity analysis of MDA-MB 231 and U87 MG cell lines showed that derivatives 7b, 7d, and 7c displayed lower IC50 values compared to albendazole (ABZ), the control. These piperazine benzimidazoles effectively reduced cell migration in both cell lines, with compound 7c exhibiting the most significant reduction, making it a promising candidate for further study. The binding mode of the most promising compound 7c, was determined using the induced fit docking–molecular dynamics (IFD–MD) approach. Regular docking and IFD were also employed for comparison. The IFD–MD analysis revealed that 7c binds to tubulin in a unique binding cavity near that of ABZ, but the benzimidazole ring was fitted much deeper into the binding pocket. Finally, the absolute free energy of perturbation technique was applied to evaluate the 7c binding affinity, further confirming the observed binding mode.
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    Peptide-based targeted cancer therapeutics: Design, synthesis and biological evaluation
    (2022-09-01) Iwanov I.; Rossi A.; Montesi M.; Doytchinova I.; Sargsyan A.; Momekov G.; Panseri S.; Naydenova E.
    Cancer is the leading cause for human mortality together with cardiovascular diseases. Abl (Abelson) tyrosine kinases play a fundamental role in transducing various signals that control proliferation, survival, migration and invasion in several cancers such as Chronic Myeloid Leukemia (CML), breast cancer and brain cancer. For these reasons Abl tyrosine kinases are considered important biological targets in drug discovery. In this study a series of lysine-based oligopeptides with expected Abl inhibitory activity were designed resembling the binding of FDA-approved drugs (i.e. of Imatinib and Nilotinib), synthesized, purified by High Performance Liquid Chromatography (HPLC), analyzed by mass spectrometry (MS) and biologically tested in vitro in CML (AR-230 and K-562), breast cancers (MDA-MB 231 and MDA-MB 468) and glioblastoma cell lines (U87 and U118). The solid-phase peptide synthesis (SPPS) by Fmoc (9-fluorenylmethoxycarbonyl) chemistry was used to synthesize target compounds. AutoDock Vina was applied for simulation binding to Abl. The biological activities were measured evaluating cytotoxic effect, induction of apoptosis and inhibition of cancer cells migration. The new peptides exhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 72 h treatment. The most promising results were obtained with the U87 glioblastoma cell line where a significant reduction of the migration ability was detected with one compound (H-Lys1-Lys2-Lys3-NH2).