Kubutin A

The two substituted 1,2,3,4-tetrahydronaphthalenes, methyl (R)-3-{(1R,4S)-6-methoxy-4,7-dimethyl-5,8-bis[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}butanoate, C36H66O5Si2, (2), and methyl (E)-3-{(1R,4S)-8-hydroxy-6-methoxy-4,7-dimethyl-5-[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acrylate, C26H42O5Si, (8), crystallize in the Sohncke space groups P212121 and P21, respectively, with the absolute structure determined on the basis of anomalous dispersion effects. The configurations of the stereo centres in the 1,2,3,4-tetrahydronaphthalene moiety of (2) and (8) are the same, and the conformation of the non-aromatic part of the ring system is nearly identical. In the crystal of (2), weak non-classical C—H...O interactions consolidate the packing, whereas in (8), intermolecular O—H...O hydrogen-bonding interactions of medium-to-weak strength direct the molecules into Z-shaped strands extending parallel to [010].

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor–mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gα t proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gα t released by Tas2R activation complexes with AChR and blocks the Gα q cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gα q -associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.