학술논문
Azetidin-2-one-based small molecules as dual hHDAC6/HDAC8 inhibitors: Investigation of their mechanism of action and impact of dual inhibition profile on cell viability.
Document Type
Academic Journal
Author
Federico S; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Khan T; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Fontana A; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Brogi S; Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.; Benedetti R; Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.; Sarno F; Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.; Carullo G; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Pezzotta A; Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA - Via Fratelli Cervi 93, 20090, Segrate (MI), Italy.; Saraswati AP; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Passaro E; Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.; Pozzetti L; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Papa A; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Relitti N; IRBM Science Park, Via Pontina Km 30,600, 00071, Pomezia, Rome, Italy.; Gemma S; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Butini S; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Pistocchi A; Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA - Via Fratelli Cervi 93, 20090, Segrate (MI), Italy.; Ramunno A; Department of Pharmacy, University of Salerno, 84084, Fisciano (SA), Italy.; Vincenzi F; Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy.; Varani K; Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy.; Tatangelo V; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Patrussi L; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Baldari CT; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Saponara S; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Gorelli B; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Lamponi S; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy.; Valoti M; Department of Life Sciences, University of Siena, 53100, Siena, Italy.; Saccoccia F; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), 00015, Monterotondo, (Rome), Italy.; Giannaccari M; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), 00015, Monterotondo, (Rome), Italy.; Ruberti G; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), 00015, Monterotondo, (Rome), Italy.; Herp D; Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, 79104, Freiburg, Germany.; Jung M; Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, 79104, Freiburg, Germany.; Altucci L; Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy; BIOGEM, Molecular Biology and Genetics Research Institute, Ariano Irpino (AV), Italy. Electronic address: lucia.altucci@unicampania.it.; Campiani G; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, 53100, Siena, Italy. Electronic address: campiani@unisi.it.
Source
Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual hHDAC6/hHDAC8 inhibition profile were developed. The dual inhibitor design investigated the diphenyl-azetidin-2-one scaffold, typified in three different structural families, that, combined to a slender benzyl linker (6c, 6i, and 6j), displays nanomolar inhibition potency against hHDAC6 and hHDAC8 isoforms. Notably, their selective action was also corroborated by measuring their low inhibitory potency towards hHDAC1 and hHDAC10. Selectivity of these compounds was further demonstrated in human cell-based western blots experiments, by testing the acetylation of the non-histone substrates alpha-tubulin and SMC3. Furthermore, the compounds reduced the proliferation of colorectal HCT116 and leukemia U937 cells, after 48 h of treatment. The toxicity of the compounds was evaluated in rat perfused heart and in zebrafish embryos. In this latter model we also validated the efficacy of the dual hHDAC6/hHDAC8 inhibitors against their common target acetylated-alpha tubulin. Finally, the metabolic stability was verified in rat, mouse, and human liver microsomes.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)