title: Characterization of the Fluorescence Properties of 4-Dialkylaminochalcones and Investigation of the Cytotoxic Mechanism of Chalcones.
abstract: Understanding the mechanisms responsible for the various biological activities of chalcones, particularly the direct cellular targets, presents an unmet challenge. Here, we prepared a series of fluorescent chalcone derivatives as chemical probes for their mechanistic investigation. Upon systematic physicochemical characterization, we explored their potential to elucidate the mode of action of chalcones' cytotoxicity. The fluorescence of the chalcones was found to be highly sensitive to structural and environmental factors. Structurally, a 4-dialkylamino group on the B ring, suitable electronic properties of the A ring substituents, and the planar conformation of the chalcone's core structure were essential for optimal fluorescence. Environmental factors influencing fluorescence included solvent polarity, pH, and the interactions of the chalcones with proteins and detergents. It was found that 18 chalcones showed a fluorescent brightness greater than 6000 M(-1)  cm(-1) in DMSO. However, water dramatically quenched the fluorescence, although it could be partially recovered in the presence of BSA or detergents. As expected, these fluorescent chalcones showed a sharp structure-activity relationship in their cellular cytotoxicity, leading to the identification of structurally similar cytotoxic and non-cytotoxic fluorescent chalcones as chemical probes. Confocal microscopy results revealed the co-localization of the cytotoxic probe C8 and tubulin in cells, supporting tubulin as the direct cellular target responsible for the cytotoxicity of chalcones.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Peixin
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005453:Fluorescence; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D003603:Cytotoxins; D014404:Tubulin
keywords: Chalcone; Cytotoxicity; Fluorescent probe; Tubulin