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

Juan Wang; Qiang Wang; Kun Wei; Xiaojuan Pan; Xuan Liu; Xiongwen Zhang; Xianrong Cai; Meng Fan; Chunru Cheng

doi:10.1016/j.bmcl.2025.130420

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

Juan Wang
, Qiang Wang
, Kun Wei
, Xiaojuan Pan
, Xuan Liu
, Xiongwen Zhang
, Xianrong Cai^*
, Meng Fan^*
, Chunru Cheng

^*此作品的通讯作者

Sichuan University of Science & Engineering
East China Normal University
Shanghai University of Traditional Chinese Medicine

科研成果: 期刊稿件 › 文章 › 同行评审

摘要

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.

源语言	英语
期刊论文编号	130420
期刊	Bioorganic and Medicinal Chemistry Letters
卷	130
DOI	https://doi.org/10.1016/j.bmcl.2025.130420
出版状态	已出版 - 1 1月 2026

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10.1016/j.bmcl.2025.130420

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title = "Synthesis, structure{\textendash}activity relationships of carnosol derivatives for cancer-associated cachexia",

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.",

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author = "Juan Wang and Qiang Wang and Kun Wei and Xiaojuan Pan and Xuan Liu and Xiongwen Zhang and Xianrong Cai and Meng Fan and Chunru Cheng",

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AU - Wang, Juan

AU - Wang, Qiang

AU - Wei, Kun

AU - Pan, Xiaojuan

AU - Liu, Xuan

AU - Zhang, Xiongwen

AU - Cai, Xianrong

AU - Fan, Meng

AU - Cheng, Chunru

PY - 2026/1/1

Y1 - 2026/1/1

N2 - 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.

AB - 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.

KW - Cancer-associated Cachexia

KW - Carnosol

KW - Structure–activity relationship

UR - https://www.scopus.com/pages/publications/105017690155

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DO - 10.1016/j.bmcl.2025.130420

M3 - 文章

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AN - SCOPUS:105017690155

SN - 0960-894X

VL - 130

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 130420

ER -

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

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