Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy

On
the basis of the synergism of topoisomerase (Top) and histone
deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel
Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore
fusion strategy. After systematic structure–activity relationship
studies, lead compound 16j was identified to simultaneously
inhibit both Top and HDAC with good potency, which showed potent antiproliferative
activities with a broad spectrum. Mechanistic studies indicated that
compound 16j efficiently induced apoptosis with S cell-cycle
arrest in HEL cancer cells. It was orally active in HEL xenograft
models and exhibited excellent in vivo antitumor
efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights
the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors
and provides a valuable lead compound for the development of novel
antitumor agents for leukemia therapy.