2. Academic Validation
  3. Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer

Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer

  • J Med Chem. 2020 Jan 23;63(2):696-713. doi: 10.1021/acs.jmedchem.9b01626.
Lei Wang 1 2,  Kun Fang 1,  Junfei Cheng 1,  Yu Li 1,  Yahui Huang 1,  Shuqiang Chen 1,  Guoqiang Dong 1,  Shanchao Wu 1,  Chunquan Sheng 1 2 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China.
  • 2 School of Pharmacy , Fujian University of Traditional Chinese Medicine , 1 Qiuyang Road , Fuzhou , Fujian 350122 , China.
  • 3 School of Pharmaceutical Sciences , Zhengzhou University , Zhengzhou 450001 , China.
PMID: 31880942 DOI: 10.1021/acs.jmedchem.9b01626
Abstract

Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of Topoisomerase 1 and tubulin and induced Apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.

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