Total synthesis and target identification of marine cyclopiane diterpenes
Abstract Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy coni...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55189-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559332599103488 |
|---|---|
| author | Tian Li Shan Jiang Yuanhao Dai Xia Wu Huihui Guo Liang Shi Xueli Sang Li Ren Jie Wang Lili Shi Wenming Zhou Houhua Li Hong-Dong Hao |
| author_facet | Tian Li Shan Jiang Yuanhao Dai Xia Wu Huihui Guo Liang Shi Xueli Sang Li Ren Jie Wang Lili Shi Wenming Zhou Houhua Li Hong-Dong Hao |
| author_sort | Tian Li |
| collection | DOAJ |
| description | Abstract Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy conidiogenone C, and identification of Immunity-related GTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetric synthesis commences from Wieland-Miescher ketone and features a sequential intramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization to rapidly construct the 6-5-5-5 tetracyclic skeleton. The stereocontrolled cyclopentenone construction is further investigated on complex settings to demonstrate its synthetic utility. Furthermore, using an alkyne-tagged conidiogenone C-derived probe, IRGM1, a master regulator of type I interferon responses, is identified as a key cellular target of conidiogenone C responsible for its anti-inflammatory activity. Preliminary mechanism of action studies shows that conidiogenone C activates IRGM1-mediate dysfunctional mitochondria autophagy to maintain mitochondria quality control of inflammatory macrophages. |
| format | Article |
| id | doaj-art-022dfb42a14348068d93f424a1d497b3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-022dfb42a14348068d93f424a1d497b32025-01-05T12:34:48ZengNature PortfolioNature Communications2041-17232024-12-0115111410.1038/s41467-024-55189-8Total synthesis and target identification of marine cyclopiane diterpenesTian Li0Shan Jiang1Yuanhao Dai2Xia Wu3Huihui Guo4Liang Shi5Xueli Sang6Li Ren7Jie Wang8Lili Shi9Wenming Zhou10Houhua Li11Hong-Dong Hao12Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityState Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityState Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityState Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate SchoolShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityState Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking UniversityShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F UniversityAbstract Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy conidiogenone C, and identification of Immunity-related GTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetric synthesis commences from Wieland-Miescher ketone and features a sequential intramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization to rapidly construct the 6-5-5-5 tetracyclic skeleton. The stereocontrolled cyclopentenone construction is further investigated on complex settings to demonstrate its synthetic utility. Furthermore, using an alkyne-tagged conidiogenone C-derived probe, IRGM1, a master regulator of type I interferon responses, is identified as a key cellular target of conidiogenone C responsible for its anti-inflammatory activity. Preliminary mechanism of action studies shows that conidiogenone C activates IRGM1-mediate dysfunctional mitochondria autophagy to maintain mitochondria quality control of inflammatory macrophages.https://doi.org/10.1038/s41467-024-55189-8 |
| spellingShingle | Tian Li Shan Jiang Yuanhao Dai Xia Wu Huihui Guo Liang Shi Xueli Sang Li Ren Jie Wang Lili Shi Wenming Zhou Houhua Li Hong-Dong Hao Total synthesis and target identification of marine cyclopiane diterpenes Nature Communications |
| title | Total synthesis and target identification of marine cyclopiane diterpenes |
| title_full | Total synthesis and target identification of marine cyclopiane diterpenes |
| title_fullStr | Total synthesis and target identification of marine cyclopiane diterpenes |
| title_full_unstemmed | Total synthesis and target identification of marine cyclopiane diterpenes |
| title_short | Total synthesis and target identification of marine cyclopiane diterpenes |
| title_sort | total synthesis and target identification of marine cyclopiane diterpenes |
| url | https://doi.org/10.1038/s41467-024-55189-8 |
| work_keys_str_mv | AT tianli totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT shanjiang totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT yuanhaodai totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT xiawu totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT huihuiguo totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT liangshi totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT xuelisang totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT liren totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT jiewang totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT lilishi totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT wenmingzhou totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT houhuali totalsynthesisandtargetidentificationofmarinecyclopianediterpenes AT hongdonghao totalsynthesisandtargetidentificationofmarinecyclopianediterpenes |