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

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 AUC_0-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.