10. Total synthesis and target identification of marine cyclopiane diterpenes

Marine cyclopianes are a family ofditerpenoid with novel carbon skeleton and diverse biological activities.Herein, we report our synthetic and chemical proteomics studies of cyclopianediterpenes which culminate in the asymmetric total synthesis of conidiogenonesC, K and 12β-hydroxy conidiogenone C, and identification of Immunity-relatedGTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetricsynthesis commences from Wieland-Miescher ketone and features a sequentialintramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization torapidly construct the 6-5-5-5 tetracyclic skeleton. The stereocontrolledcyclopentenone construction is further investigated on complex settings todemonstrate its synthetic utility. Furthermore, using an alkyne-taggedconidiogenone C-derived probe, IRGM1, a master regulator of type I interferonresponses, is identified as a key cellular target of conidiogenone Cresponsible for its anti-inflammatory activity. Preliminary mechanism of actionstudies shows that conidiogenone C activates IRGM1-mediate dysfunctionalmitochondria autophagy to maintain mitochondria quality control of inflammatorymacrophages.