Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties

  • J Med Chem. 2018 Feb 8;61(3):760-776. doi: 10.1021/acs.jmedchem.7b01259.
Chunyong Ding  1  2 ,  Qianting Tian  3  2 ,  Jie Li  1  4 ,  Mingkun Jiao  1 ,  Shanshan Song  3 ,  Yingqing Wang  3  2 ,  Zehong Miao  3  2 ,  Ao Zhang  1  3  4  2
Affiliations
  • 1. CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences , Beijing 100049, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
  • 4. ShanghaiTech University , Shanghai 20120, China.
PMID: 29294282 DOI: 10.1021/acs.jmedchem.7b01259
Abstract

The clinical development of natural product tanshinone I (1) for Cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR Cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced Apoptosis of HCT116 cells, at least partially, through activation of Caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice.

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