Lingzhiols, Unprecedented Rotary Door-Shaped Meroterpenoids as Potent and Selective Inhibitors of p-Smad3 from Ganoderma lucidum

Abstract

(+)-Lingzhiol and (-)-lingzhiol, a pair of rotary door-shaped meroterpenoidal enantiomers, were isolated from Ganoderma lucidum. Their structures were identified by spectroscopic methods and X-ray diffraction crystallography. Lingzhiol bears an unusual 5/5/6/6 ring system characteristic of sharing a C-3'-C-7' axis. Biological evaluation showed that (+)-lingzhiol or (-)-lingzhiol could selectively inhibit the phosphorylation of Smad3 in TGF-β1-induced rat renal proximal tubular cells and activate Nrf2/Keap1 in mesangial cells under diabetic conditions.

Asymmetric total synthesis of (−)-lingzhiol via a Rh-catalysed [3+2] cycloaddition

“…G. lucidum is a well-known ARTICLE mushroom that is used extensively in Asia as a super-grade medicine. Biological studies of the chemicals contained in this mushroom have indicated that both of the enantiomers of lingzhiols show potent and selective inhibitory activity towards the phosphorylation of Smad3 in transforming growth factor-b1-induced rat renal proximal tubular cells and activate Nrf2/Keap1 in mesangial cells under diabetic conditions 4 . In light of the important biological activities of lingzhiol-type compounds and their potential application as lead compound for the development of therapeutic agents against chronic kidney disease, there is an urgent need for the development of a synthetic method capable of providing facile access to these materials to allow for detailed studies of their structure-activity relationship.…”

“…The structure of 10b was confirmed by X-ray crystallographic analysis. We also investigated the application of our newly developed reaction as a general method for the construction of [4,3,0] ring systems (Table 3). Enynols 15a-19a were prepared and subjected to the optimized reaction conditions to afford the corresponding products 15b-19b in good-to-acceptable yields, bearing two syn-configured vicinal quaternary stereocentres.…”

“…To demonstrate the utility of our newly developed methodology, we applied the annulation reaction in the asymmetric total synthesis of ( À )-lingzhiol (4) 4 . As a pair of rotary door-shaped meroterpenoidal enantiomers, ( À )-lingzhiol (4) and its enantiomer ( þ )-lingzhiol were isolated from Ganoderma lucidum by Hou and colleagues 4 , who had to use 80 kg of G. lucidum to obtain 25 mg of both pure ( À )-lingzhiol and ( þ )-lingzhiol. G. lucidum is a well-known ARTICLE mushroom that is used extensively in Asia as a super-grade medicine.…”

“…Crinipellin A (2), isolated from the fungus Crinipellis stipitaria (Agaricales), has been reported to exhibit potent antibiotic activity 2 . Retigeranic acid (3) is a representative member of the sesterterpenoid family of compounds and exhibits a broad range of biological activities [3][4][5][6][7] . Although compounds of this type are well known to elicit a variety of interesting biological responses, efficient methods for their construction are scarce.…”

“…Notably, the use of chiral starting materials in this reaction led to the unprecedented synthesis of enantiomerically pure [3.3.0] bicyclic products, representing a significant development in terms of the application of this reaction to the total synthesis of naturally occurring biologically active chiral molecules. Furthermore, this newly developed reaction has been successfully applied to the total synthesis of natural product lingzhiol, which is reported to be an important agent for the study and treatment of diabetic nephropathy 4 .…”