Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies

Autor: Simone Brogi, Dora Mariagrazia Cucinella, Daniel Herp, Giuseppe Campiani, Ettore Novellino, Johanna Senger, Concetta Iside, Angela Nebbioso, Lucia Altucci, Christophe Romier, Giulia Chemi, Alessandro Grillo, Stefania Butini, Stefania Lamponi, Margherita Brindisi, Sandra Gemma, Tajith B. Shaik, Federica Sarno, Caterina Cavella, Manfred Jung
Přispěvatelé: Dipartimento di Biologia e Patologia Cellulare e Moleculare, Università degli studi di Napoli Federico II, Department of Pharmacy Naples, Université de Naples, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Research Centre for Drug Discovery and Development, Banchi di Sotto 55 and Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena = University of Siena (UNISI), Dip. Patologia generale, Seconda Università di Napoli, Brindisi, Margherita, Senger, Johanna, Cavella, Caterina, Grillo, Alessandro, Chemi, Giulia, Gemma, Sandra, Cucinella, Dora Mariagrazia, Lamponi, Stefania, Sarno, Federica, Iside, Concetta, Nebbioso, Angela, Novellino, Ettore, Shaik, Tajith Baba, Romier, Christophe, Herp, Daniel, Jung, Manfred, Butini, Stefania, Campiani, Giuseppe, Altucci, Lucia, Brogi, Simone
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Models
Molecular
Cell
Apoptosis
Histone Deacetylase 1
Drug Screening Assays
Histone Deacetylase 6
0302 clinical medicine
Models
Cell Movement
HDAC
Drug Discovery
ComputingMilieux_MISCELLANEOUS
Tumor
Molecular Structure
Chemistry
Cell Cycle
Epigenetic
Enzyme inhibitors
Cell migration
Antitumor agents
Bioinformatics
Drug design
Epigenetics
Antineoplastic Agents
Cell Line
Tumor
Cell Proliferation
Dose-Response Relationship
Drug
Drug Screening Assays
Antitumor
Histone Deacetylase Inhibitors
Humans
Structure-Activity Relationship
General Medicine
Enzyme inhibitor
3. Good health
medicine.anatomical_structure
Biochemistry
030220 oncology & carcinogenesis
Drug
Cell Line
Dose-Response Relationship
03 medical and health sciences
Histone H3
medicine
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Bioinformatic
Pharmacology
Drug Discovery3003 Pharmaceutical Science
Organic Chemistry
Antitumor agent
Molecular
Antitumor
HDAC6
HDAC1
030104 developmental biology
Acetylation
Cancer cell
Zdroj: European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry, Elsevier, 2018, 157, pp.127-138. ⟨10.1016/j.ejmech.2018.07.069⟩
ISSN: 0223-5234
1768-3254
DOI: 10.1016/j.ejmech.2018.07.069⟩
Popis: This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b, with a spiroindoline-based hydroxamate bearing a tert-butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents.
Databáze: OpenAIRE
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