Structure-activity relationships of cryptopleurine analogs with E-ring modifications as anti-hepatitis C virus agents

  • Bioorg Med Chem. 2018 Feb 1;26(3):630-636. doi: 10.1016/j.bmc.2017.12.027.
Ying Wang  1 ,  Shao-Ru Chen  2 ,  Xiaoming Yang  3 ,  Kuo-Hsiung Lee  4 ,  Yung-Chi Cheng  5
Affiliations
  • 1. Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States; Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau.
  • 2. Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau.
  • 3. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
  • 4. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: [email protected].
  • 5. Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: [email protected].
PMID: 29317151 DOI: 10.1016/j.bmc.2017.12.027
Abstract

The tylophorine analog rac-cryptopleurine exhibited potent anti-hepatitis C virus (HCV) activity through allosteric regulation of ATPase activity of heat shock cognate protein 70 (Hsc70). We evaluated the impact of modifications on the E-ring of rac-cryptopleurine to the inhibitory activity against HCV replication and regulation of ATPase activity of Hsc70. Cryptopleurine analog YXM-110 with a 13α-hydroxyl group maintained activity against HCV and promoted ATP/ADP turnover of Hsc70; however, compounds with hydroxyl groups at Other positions or with Other orientations (YXM-109, YXM-139, and YXM-140) did not exhibit similar activities. Size modification or heteroatom incorporation of the E-ring led to loss of anti-HCV activity. Promotion of the chaperone activity of Hsc70 with carboxyl terminus Hsc70 interacting protein (CHIP) further enhanced the anti-HCV activity of rac-cryptopleurine and XYM-110. This structure-activity relationship (SAR) study refined structural design and optimization for developing rac-crytopleurine analogs as potent anti-HCV agents targeted against the host factor involved in HCV replication.