Hélio L Barros, Margarida Espadinha, Sandra N Pinto, Ricardo J F Ferreira, Joana B Loureiro, Rita Silva, Lucília Saraiva, Ermelinda Maçôas, Maria M M Santos
{"title":"用于 p53 激活剂细胞定位研究的色醇衍生噁唑异吲哚啉酮荧光探针。","authors":"Hélio L Barros, Margarida Espadinha, Sandra N Pinto, Ricardo J F Ferreira, Joana B Loureiro, Rita Silva, Lucília Saraiva, Ermelinda Maçôas, Maria M M Santos","doi":"10.1016/j.bioorg.2024.107898","DOIUrl":null,"url":null,"abstract":"<p><p>The protein p53 is a transcription factor with several key roles in cells, including acting as a tumour suppressor. In most human cancers its tumour suppressor function is inactivated, either through inhibition by negative regulators or by mutation in the TP53 gene. Thus, there is a high interest in developing molecules able to activate p53 tumour suppressor activity. Tryptophanol-derived isoindolinones are known to act as wild-type and mutant p53 activators. Specifically, SLMP53-1 is a non-fluorescent wild-type and mutant p53 R280K reactivator, with potent in vivo anti-tumour activity in HCT116 and MDA-MB-231 mice xenograft models. With the aim of studying tryptophanol-derived isoindolinones intracellular localization by fluorescence microscopy, three SLMP53-1 based fluorescent probes were prepared. Here we report the design, synthesis, photophysical characterization, antiproliferative activity and cell localization studies of these fluorescent probes. The previously described structure-activity relationships of the SLMP53-1 scaffold set the basis for the design the fluorescent probes. The probes were prepared by connecting a small fluorophore (dansyl or 7-nitrobenzofurazan) to the indole nitrogen of the tryptophanol-derived oxazoloisoindolinone SLMP53-1 through two different linkers. The antiproliferative activity and cell localization studies of the three fluorescent probes were performed in HCT116 cells. The three probes showed enhanced internalization when compared with their fluorophore-linker intermediates, good photo-stability and high affinity for the endoplasmic reticulum, indicating the potential involvement of endoplasmic reticulum in the mechanism of action of tryptophanol-derived oxazoloisoindolinones.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107898"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tryptophanol-derived oxazoloisoindolinone fluorescent probes for cellular localization studies of p53 activators.\",\"authors\":\"Hélio L Barros, Margarida Espadinha, Sandra N Pinto, Ricardo J F Ferreira, Joana B Loureiro, Rita Silva, Lucília Saraiva, Ermelinda Maçôas, Maria M M Santos\",\"doi\":\"10.1016/j.bioorg.2024.107898\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The protein p53 is a transcription factor with several key roles in cells, including acting as a tumour suppressor. 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The probes were prepared by connecting a small fluorophore (dansyl or 7-nitrobenzofurazan) to the indole nitrogen of the tryptophanol-derived oxazoloisoindolinone SLMP53-1 through two different linkers. The antiproliferative activity and cell localization studies of the three fluorescent probes were performed in HCT116 cells. 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Tryptophanol-derived oxazoloisoindolinone fluorescent probes for cellular localization studies of p53 activators.
The protein p53 is a transcription factor with several key roles in cells, including acting as a tumour suppressor. In most human cancers its tumour suppressor function is inactivated, either through inhibition by negative regulators or by mutation in the TP53 gene. Thus, there is a high interest in developing molecules able to activate p53 tumour suppressor activity. Tryptophanol-derived isoindolinones are known to act as wild-type and mutant p53 activators. Specifically, SLMP53-1 is a non-fluorescent wild-type and mutant p53 R280K reactivator, with potent in vivo anti-tumour activity in HCT116 and MDA-MB-231 mice xenograft models. With the aim of studying tryptophanol-derived isoindolinones intracellular localization by fluorescence microscopy, three SLMP53-1 based fluorescent probes were prepared. Here we report the design, synthesis, photophysical characterization, antiproliferative activity and cell localization studies of these fluorescent probes. The previously described structure-activity relationships of the SLMP53-1 scaffold set the basis for the design the fluorescent probes. The probes were prepared by connecting a small fluorophore (dansyl or 7-nitrobenzofurazan) to the indole nitrogen of the tryptophanol-derived oxazoloisoindolinone SLMP53-1 through two different linkers. The antiproliferative activity and cell localization studies of the three fluorescent probes were performed in HCT116 cells. The three probes showed enhanced internalization when compared with their fluorophore-linker intermediates, good photo-stability and high affinity for the endoplasmic reticulum, indicating the potential involvement of endoplasmic reticulum in the mechanism of action of tryptophanol-derived oxazoloisoindolinones.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.