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

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.

Comparative Characterization of the Leaf Tissue of Physalis alkekengi and Physalis peruviana Using RNA-seq and Metabolite Profiling

“…An error bar indicates standard deviation. The authentic compounds used in this analysis were chemically synthesized as described in our previous paper (Ozawa et al, 2013). The limit of detection of each sample was 0.011923 ( P. alkekengi , d15_Young), 0.010910 ( P. alkekengi , d20_Mature), 0.013556 ( P. alkekengi , d22_Mid), 0.010820 ( P. alkekengi , d27_Mature), 0.010884 ( P. alkekengi , d30_Mid), 0.012211 ( P. peruviana , d15_Mature), 0.012456 ( P. peruviana , d22_Mature), 0.012366 ( P. peruviana , d29_Mature), 0.014794 ( P. peruviana , d65_Young), and 0.013141 ( P. peruviana , d65_Mature).…”

“…The authentic samples of withanolides were isolated from plants as described in our previous paper (Ozawa et al, 2013). The leaves of P. alkekengi and P. peruviana were collected at five different developmental stages of the growing season before bearing fruit, because our pilot study showed to detect withanolides of P. alkekengi and P. peruviana at these stages (data not shown).…”

“…Studies using spectroscopic methods isolated 3 new- and 7 known steroids including physalins and demonstrated that physalin B exhibited the most significant cytotoxic activities against HeLa human cervical cells (Kawai et al, 2002; Li et al, 2014). Physalin B or F inhibited NF-kappa B activation (Jacobo-Herrera et al, 2006; Wu et al, 2012) and both right- and left-sided partial structures were proposed to play a significant role in their mode of action (Ozawa et al, 2013). 4β-Hydroxywithanolide E derived from P. peruviana inhibited the growth of a human non-small lung cancer cell line (Yen et al, 2010).…”

Synthesis of the Right‐Side Structure of Type B Physalins

“…We have already succeeded in synthesizing the cage‐shaped molecule 3 (Scheme ),, and we confirmed that the right‐side structure of physalins indeed contributes to NF‐κB‐inhibitory activity . The synthesis of 3 featured precise construction of tricyclic key intermediate 8 through a Diels−Alder reaction and the installation of two C1 units, and its “domino ring transformation”, leading to DEFGH‐ring compound 3 .…”

Mimicking/Extracting Structure and Functions of Natural Products: Synthetic Approaches that Address Unexplored Needs in Chemical Biology

“…Thus, the benzyl group was employed as a protective group for the secondary alcohol at C13 and could be removed by hydrogenolysis to give 42 . Moreover, by utilizing the instability of the H ring, the benzyl‐protected right‐side partial structure of type A physalins (PAright‐1, 62 ) was also synthesized [35]…”