In this work, we
described the synthesis of 10 new fluorescent
2,1,3-benzoselenadiazole small-molecule derivatives and their chemical-
and photocharacterizations. The new derivatives could, for the first
time, be successfully applied as selective live cell imaging probes
(at nanomolar concentrations) and stained lipid-based structures preferentially.
Density functional theory (DFT) calculations were used to help in
understanding the photophysical data and the intramolecular charge-transfer
(ICT) processes of the synthesized dyes. Some derivatives showed impressive
cellular responses, allowing them to be tested as probes in a complex
multicellular model (i.e., Caenorhabditis elegans). When compared with the commercially available dye, the new fluorescent
compounds showed far better results both at the cellular level and
inside the live worm. Inside the multicellular complex model, the
tested probes also showed selectivity, a feature not observed when
the commercial dye was used to carry out the bioimaging experiments.
Triple-negative breast cancer (TNBC) constitutes a very aggressive type of breast cancer with few options of cytotoxic chemotherapy available for them. A chemotherapy regimen comprising of doxorubicin hydrochloride and cyclophosphamide, followed by paclitaxel, known as AC-T, is approved for usage as an adjuvant treatment for this type of breast cancer. In this study we aimed to elucidate the role of KIF11 in TNBC progression throughout its inhibition by two synthetic small molecules containing the DHPM core (dihydropyrimidin-2(1H)-ones or -thiones), with the hypothesis that these inhibitors could be an interesting option of antimitotic drug used alone or as adjuvant therapy in association with AC. For this purpose, we evaluated the efficacy of DHPMs used as monotherapy or in combination with doxorubicin and cyclophosphamide, in Balbc-nude mice bearing breast cancer induced by MDA-MB-231, having AC-T as positive control. Our data provide extensive evidence to demonstrate that KIF11 inhibitors showed pronounced antitumor activity, acting in key points of tumorigenesis and cancer progression in in vivo xenograft model of triple negative breast cancer, like down-regulation of KIF11 and ALDH1-A1. Moreover, they didn't show the classic peripheral neuropathy characterized by impaired mobility, as it is common with paclitaxel use. These results suggest that the use of a MAP inhibitor in breast cancer regimen treatment could be a promising strategy to keep antitumoral activity reducing the side effects.
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