Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors

  • ACS Med Chem Lett. 2015 Jan 14;6(3):239-43. doi: 10.1021/ml500327q.
Shipeng He  1 ,  Guoqiang Dong  2 ,  Zhibin Wang  2 ,  Wei Chen  2 ,  Yahui Huang  2 ,  Zhengang Li  2 ,  Yan Jiang  2 ,  Na Liu  2 ,  Jianzhong Yao  2 ,  Zhenyuan Miao  2 ,  Wannian Zhang  2 ,  Chunquan Sheng  3
Affiliations
  • 1. School of Pharmacy, Fujian University of Traditional Chinese Medicine , 1 Qiuyang Road, Fuzhou, Fujian 350122, P. R. China.
  • 2. School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, P. R. China.
  • 3. School of Pharmacy, Fujian University of Traditional Chinese Medicine , 1 Qiuyang Road, Fuzhou, Fujian 350122, P. R. China ; School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, P. R. China.
PMID: 25815139 DOI: 10.1021/ml500327q
Abstract

Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between Topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of Topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of Topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple Topoisomerase I/II and HDAC inhibitors as novel antitumor agents.

Keywords
Evodiamine derivatives; antiproliferative activity; histone deacetylase; topoisomerase I; topoisomerase II.