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

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 N 1-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. Graphical abstract Image 1 Highlights • Rational design of novel spiroindoline as HDAC6 inhibitors. • Biological studies showed a strong antitumor potential for the synthesized compounds. • Compound 5b was able to potently inhibit cell migration in a SH-SY5Y cell culture. • Compound 5b did not display toxicity in NIH3T3 mouse fibroblasts. [ABSTRACT FROM AUTHOR]