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.
|Titolo:||Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies|
BUTINI, STEFANIA (Corresponding)
|Rivista:||EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY|
|Citazione:||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.|
|Appare nelle tipologie:||1.1 Articolo in rivista|