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

• Published in: Journal of medicinal chemistry Vol. 61; no. 3; pp. 760 - 776
• Main Authors: Ding, Chunyong, Tian, Qianting, Li, Jie, Jiao, Mingkun, Song, Shanshan, Wang, Yingqing, Miao, Zehong, Zhang, Ao
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.02.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; IIA; INHIBITION; PHARMACOKINETICS; PROSTATE-CANCER CELLS; GROWTH; SALVIA-MILTIORRHIZA BUNGE; DIHYDROTANSHINONE-I; INDUCTION; CRYPTOTANSHINONE; MASS-SPECTROMETRY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01259

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 (T 1/2 = 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.