Contribution of Cage-Shaped Structure of Physalins to Their Mode of Action in Inhibition of NF-κB Activation

  • ACS Med Chem Lett. 2013 Jun 6;4(8):730-5. doi: 10.1021/ml400144e.
Masaaki Ozawa  1 ,  Masaki Morita  2 ,  Go Hirai  1 ,  Satoru Tamura  3 ,  Masao Kawai  4 ,  Ayako Tsuchiya  5 ,  Kana Oonuma  1 ,  Keiji Maruoka  6 ,  Mikiko Sodeoka  7
Affiliations
  • 1. Synthetic Organic Chemistry Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan ; RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 2. Synthetic Organic Chemistry Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan ; Department of Chemistry, Graduate School of Science, Kyoto University , Sakyo, Kyoto 606-8502, Japan.
  • 3. Synthetic Organic Chemistry Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan ; ERATO-JST , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 4. Nagoya Institute of Technology , Gokiso-cho, Showa-ku, Nagoya, Aichi 466-8555, Japan ; Nakanoshima Science Laboratory, Osaka Science Museum , 4-2-1 Nakanoshima, Kita-ku, Osaka 530-0005, Japan.
  • 5. Synthetic Organic Chemistry Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 6. Department of Chemistry, Graduate School of Science, Kyoto University , Sakyo, Kyoto 606-8502, Japan.
  • 7. Synthetic Organic Chemistry Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan ; RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan ; ERATO-JST , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
PMID: 24900739 DOI: 10.1021/ml400144e
Abstract

A library of oxygenated natural Steroids, including physalins, withanolides, and perulactones, coupled with the synthetic cage-shaped right-side structure of type B physalins, was constructed. SAR studies for inhibition of NF-κB activation showed the importance of both the B-ring and the oxygenated right-side partial structure. The 5β,6β-epoxy derivatives of both physalins and withanolides showed similar profiles of inhibition of NF-κB activation and appeared to act on NF-κB signaling via inhibition of phosphorylation and degradation of IκBα. In contrast, type B physalins with C5-C6 olefin functionality inhibited nuclear translocation and DNA binding of RelA/p50 protein dimer, which lie downstream of IκBα degradation, although withanolides having the same AB-ring functionality did not. These results indicated that the right-side partial structure of these Steroids influences their mode of action.

Keywords
NF-κB; Physalis plants; SAR; highly oxygenated steroid; physalin; synthetic analogues; withanolide.