Enzymatic C42 Diversification of Rapamycin Identifies a Potent Butyryl-Modified Anticancer Derivative

  • Org Lett. 2026 Mar 6;28(9):2902-2905. doi: 10.1021/acs.orglett.6c00072.
Yining Liu  1 ,  Hengyu Li  1  2 ,  Jinyue Pu  1 ,  Aiai Sun  1 ,  Hai-Xue Pan  3 ,  Gong-Li Tang  1  3
Affiliations
  • 1. Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 2. Key Laboratory of Innovation and Manufacturing for Pharmaceuticals of Guizhou Province, Key Laboratory of Basic Pharmacology of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
PMID: 41733149 DOI: 10.1021/acs.orglett.6c00072
Abstract

A highly regioselective, one-step lipase-catalyzed method enabled the diversification of rapamycin at its C42 position, producing 10 derivatives (4 novel). Biological screening identified derivative 9 as a potent lead compound with superior antiproliferative activity (IC50 = 6.5 μM in ACHN cells), outperforming both rapamycin and temsirolimus. This work offers a practical enzymatic route for rapamycin remodeling and highlights a promising mTOR-targeted Anticancer candidate.

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