Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents

  • J Med Chem. 2015 Aug 27;58(16):6678-96. doi: 10.1021/acs.jmedchem.5b00910.
Shengzheng Wang  1  2 ,  Kun Fang  1 ,  Guoqiang Dong  1 ,  Shuqiang Chen  1 ,  Na Liu  1 ,  Zhenyuan Miao  1 ,  Jianzhong Yao  1 ,  Jian Li  3 ,  Wannian Zhang  1 ,  Chunquan Sheng  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 2. School of Pharmacy, Fourth Military Medical University , 169 Changle West Road, Xi'an, 710032, People's Republic of China.
  • 3. School of Pharmacy, East China University of Science & Technology , 130 Meilong Road, Shanghai 200237, People's Republic of China.
PMID: 26226379 DOI: 10.1021/acs.jmedchem.5b00910
Abstract

A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human Cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple Topoisomerase I/Topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery.

Products