2. Academic Validation
  3. Synthesis, structure-activity relationships of carnosol derivatives for cancer-associated cachexia

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

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: xianrongcai@sina.com.
  • 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: mfan@pharm.ecnu.edu.cn.
  • 6 College of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, Sichuan, PR China. Electronic address: pharmaceutics@163.com.
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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