Professor Ya-Qiu Long's group reports “Concise asymmetric total syntheses of (+)-dihydropleurotinic acid and ()-pleurotin, enabling rapid late-stage diversification”

(-)-Pleurotin (1) and (+)-dihydropleurotinic acid (2) are fungal metabolites, which have been known to display wide-spectrum anticancer effects, and potent antibiotic activities against fungi and Gram-positive bacteria. Significantly, (-)-pleurotin (1) was recently revealed to be a potent irreversible inhibitor of the thioredoxin (Trx)−thioredoxin reductase (TrxR) system with an IC₅₀ value of 170 nM, leading to a substantial reduction in the level of hypoxia-inducible factor-1α (HIF-1α) in cancer cells, thereby inhibiting the transcription of cancer-related genes which help the cancer cells adapt to the hypoxia microenvironment. Therefore, pleurotin and related benzoquinone meroterpenoids are of great interest for the therapeutical potential. Structurally, these natural products comprise a fused pentacyclic or hexacyclic core, a redox sensitive para-quinone moiety, seven to eight contiguous stereocenters (one is an all-carbon quaternary center joining four ring systems), rendering the total synthesis a highly challenging mission.

The lack of available pleurotin natural products as well as the scalable synthesis toward the fused pentacyclic scaffold has hindered its medicinal chemical study and further development into therapeutic modality. Herein, Professor Ya-Qiu Long's group report a concise and efficient asymmetric total synthesis of (+)-dihydropleurotinic acid (2) and (-)-pleurotin (1) from the known readily available (R)-Roche ester derived vinyl bromide7 in 12 and 13 steps (LLS), respectively. The key transformations feature a Michael addition/alkylation cascade reaction to forge three contiguous stereocenters matched with the natural products, a PtO₂-catalyzed stereoselective reduction of olefin to generate the correct stereocenter at C-3, a palladium-catalyzed Negishi cross coupling between triflate and zinc reagent to introduce the redox sensitive para-quinone moiety and a hydroboration/copper-catalyzed carboxylation sequence to incorporate the vital carboxyl group.

Significantly, the scalable preparation of the complete pentacyclic scaffolds of pleurotin natural products was thereby accomplished, delivering 12 pleurotin analogs via rapid late-stage diversification with remarkably improved antiproliferative activities against TrxR-1 overexpressed human breast cancer cell lines compared to the parent natural product (-)-pleurotin (1). 

Furthermore, the selectivity index data demonstrated that the pleurotin analogs 23c and 23e exhibited significant selectivity of the cytotoxicity against breast cancer cells over normal cells. Therefore, analogues 23c and 23e could serve as promising lead compounds for the further development of novel TrxR inhibitors.

Associate Professor Bin Huang from our college is the co-first author of this study, with other co-authors including doctoral student Jing Pang, master's students Nan Cao and Ya-Shuang Dai. Associate Professor Bin Huang and Professor Ya-Qiu Long from our college are the co-corresponding authors. This work was supported by the National Natural Science Foundation of China (81903442, 22377088), Natural Science Foundation of Jiangsu Province (BK20190817), Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University (YXY2304077), Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.

Reference:

Concise asymmetric total syntheses of (+)-dihydropleurotinic acid and (-)-pleurotin, enabling rapid late-stage diversification.

Bin Huang ^a⁎, Jing Pang ^a, Nan Cao ^a, Ya-Shuang Dai ^a, Ya-Qiu Long ^a⁎

Full-text link: https://doi.org/10.1021/jacsau.4c00942

Corresponding authors:

Dr. Ya-Qiu Long is a distinguished professor at the College of Pharmaceutical Sciences, Soochow University. Long’s laboratory has focused mainly on the discovery and structural optimization of tumor- and virus-targeting small molecules and peptide drugs, enriching and advancing new strategies and systems for precise diagnostic and therapeutic drug discovery. These include targeting non-enzymatic binding sites and spatiotemporally controllable chemical labeling and regulation of target proteins. She is the winners of the National Science Fund for Distinguished Young Scholars, selected for the Chinese Academy of Sciences Hundred Talents Program and the National New Century Hundred-Thousand-Ten Thousand Talent Project, and awarded the State Council Special Government Allowance.Now she is the Member of the Youth Working Committee of the 25th Council of the Chinese Pharmaceutical Association, Member of the 10th Medicinal Chemistry Committee of the Chinese Pharmaceutical Association, Expert Member of the China Biochemical Pharmaceutical Industry Association, Deputy Chairman of the Medicinal Chemistry Committee of the Jiangsu Pharmaceutical Association, Director of the Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, and Editorial Board Member of the international academic journal ChemMedChem (Wiley-VCH).

Dr. Bin Huang is an associate professor at the College of Pharmaceutical Sciences, Soochow University. Dr. Bin Huang research interests focuses on efficient synthesis of bioactive natural products and druggability modification, structure function relationship and chemical biology study of bioactive natural products. He has published more than 10 academic papers in Angew. Chem., Int. Ed.; JACS Au; J. Med. Chem.; Chem. Eur. J.