Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

• A spirochromane hydroxamate scaffold was designed and evaluated for its HDAC inhibition.
• Several inhibitors displayed potent antiproliferative activity in tumor cell lines.
• Molecular modeling studies were carried out to unravel the binding mode of these inhibitors.
• Selected compounds showed good microsomal stability.

In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4′-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.

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