Synthesis, structure-activity relationships of carnosol derivatives for cancer-associated cachexia

  • Bioorg Med Chem Lett. 2025 Sep 27:130:130420. doi: 10.1016/j.bmcl.2025.130420.
Juan Wang  1 ,  Qiang Wang  1 ,  Kun Wei  1 ,  Xiaojuan Pan  2 ,  Xuan Liu  3 ,  Xiongwen Zhang  2 ,  Xianrong Cai  4 ,  Meng Fan  5 ,  Chunru Cheng  6
Affiliations
  • 1. College of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, Sichuan, PR China.
  • 2. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
  • 3. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201003, PR China.
  • 4. College of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, Sichuan, PR China. Electronic address: [email protected].
  • 5. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; School of Pharmacy, East China Normal University, Shanghai 200062, PR China. Electronic address: [email protected].
  • 6. College of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, Sichuan, PR China. Electronic address: [email protected].
PMID: 41022184 DOI: 10.1016/j.bmcl.2025.130420
Abstract

Cancer-associated cachexia, marked by progressive muscle atrophy and metabolic dysfunction, poses a significant therapeutic challenge. To address carnosol's metabolic instability, we rationally designed 35 derivatives by replacing its oxidation-prone 11,12-phenolic groups with oxazole rings or aryl moieties. SAR-guided optimization identified 10 as the lead compound. In C26 tumor-conditioned models, 10 attenuated myotube atrophy (67.08 % reversal) and adipocyte lipolysis. In C26 tumor-bearing mice, 10 alleviated cachexia-related weight loss without altering tumor progression. Pharmacokinetic studies revealed enhanced stability: a half-life of 11.1 h and an AUC0-t of 8369 ng/mL. These results position 10 as a promising therapeutic candidate for Cancer cachexia, while offering a strategic framework for rational optimization of natural product.

Keywords
Cancer-associated Cachexia; Carnosol; Structure–activity relationship.
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