Stereoselective Synthesis and Osteogenic Activity of Subglutinols A and B

Abstract

Since clinically approved immunosuppressive drugs (e.g., cyclosporin A, FK506) possess dose-dependent biphasic effects that cause undesirable side effects on bone structure, including osteopenia, osteoporosis, and increased incidence of bone fractures, considerable effort has been devoted to the identification of immunosuppressive drugs that promote bone formation in a dose-dependent manner. Herein, we report the stereoselective synthesis of subglutinols A and B and present initial biological data showing the significant potential of subglutinol A as an immunosuppressive drug with dose-dependent osteogenic activity. We also show that activating protein 1 (AP-1) family transcription factors could be one of the key regulators for the anabolic activity of subglutinol A. Such drugs with dose-dependent osteogenic activity might help reduce bone-associated side effects and be clinically useful for bone tissue transplantation.

Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

“…The absolute configuration of the common intermediate (4) was determined by the modified Mosher's method 49 ( Supplementary Fig. 10), while those of 5, 6, 9 and 10 were identified by comparing their optical rotation with reported values 40,43 . The absolute configurations of the other DDPs were determined based on their biosynthetic relationships.…”

“…Thus, the chemical space of DDPs is likely relevant to a diverse biological space and expanding this space leads to the development of a valuable screening library for drug discovery. In addition to promising biological activities, the structural features of DDPs render them exciting targets for total synthesis [42][43][44] . Recently, excellent divergent total synthesis has been reported, which enables access to four DDPs via a common intermediate in less than twenty chemical reaction steps 45 .…”

Advances in Total Synthesis of Alternaric Acid: An Anti-Fungal and Phytotoxic Natural Product

“…It resulted in high yield along with excellent stereochemical outcome >20:1 [31][32] . In the subsequent step, dithiane 80 was cleaved followed by 1,3-syn selective reduction to yield diol 82 which under acidic conditions provided 83 33 .…”

Fungal sensing of host environment

“…In contrast, Fusarium subglutinans was found to produce subglutinol A, an immunosuppressive α-pyrone diterpenoid, which acts as an estrogen receptor antagonist with osteogenic activity (Lim et al, 2015). While it is not clear whether subglutinol A is produced by the fungus for immunevasion, the osteogenic potential of the fungal compound could be exploited for drug development avoiding or counteracting the undesirable side effect on the bone structure of currently used immunosuppresives (Kim et al, 2009). Paracoccidioides brasiliensis is known to respond to estrogen because hyphal to yeast transformation was inhibited by estrogen, explaining the resistance of women to the disease (Restrepo et al, 1984).…”