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

Abstract

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.

• Authors: Shanchao Wu, Yahui Huang, Ting Wang, Keliang Li, Junjie Lu, Min Huang, Guoqiang Dong, Chunquan Sheng
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 6 Pg. 4818-4831 (03 24 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35238576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histone Deacetylases

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Drug Design
• Drug Screening Assays, Antitumor
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histone Deacetylases (metabolism)
• Humans
• Leukemia (drug therapy)
• Structure-Activity Relationship