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.

Brindisi, M., Senger, J., Cavella, C., Grillo, A., Chemi, G., Gemma, S., et al. (2018). Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 157, 127-138 [10.1016/j.ejmech.2018.07.069].

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

Brindisi, Margherita;Cavella, Caterina;Grillo, Alessandro;Chemi, Giulia;Gemma, Sandra;Lamponi, Stefania;Butini, Stefania
;
Campiani, Giuseppe;
2018

Abstract

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.
Brindisi, M., Senger, J., Cavella, C., Grillo, A., Chemi, G., Gemma, S., et al. (2018). Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 157, 127-138 [10.1016/j.ejmech.2018.07.069].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/1058108