Spirocitromycetin, a Fungal Polyketide with an Antiosteoporotic Pharmacophore

Spirocitromycetin, an antiosteoporotic polyketide bearing a unique spirocycle, was characterized from a human mucus sputum-derived Penicillium velutinum. Its structure and absolute configuration were elucidated spectrally, with its biosynthetic pathway likely mediated via polivione, a reported heptaketide. Spirocitromycetin was shown to be antiosteoporotic at 0.1 mu M in the prednisolone-induced osteoporotic zebrafish model. A combination of spirocitromycetin variant synthesis and bioassay has identified 5 '-methyl-3 ' H-spiro[chromane-3,2 '-furan]- 3 ',4-dione as an unreported antiosteroporotic pharmacophore. Collectively, this work offers new starting (sub)structures that may be of significance for antiosteoporotic drug discovery