2. Academic Validation
  3. Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability

Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability

  • Eur J Med Chem. 2024 Jul 2:276:116646. doi: 10.1016/j.ejmech.2024.116646.
Weiping Wang 1,  Jiaqi Fan 1,  Fengxiao Li 1,  Shuo Gan 1,  Jiaming Zhang 1,  Yanfang Wang 1,  Yingchao Li 1,  Wenchao Li 1,  Zhonggui He 1,  Huaiwei Ding 2,  Yongbing Sun 3,  Tianhong Zhang 4,  Qikun Jiang 5
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Division of Pharmaceutics, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China. Electronic address: Yongbing_sun@hotmail.com.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: zhangth1058@aliyun.com.
  • 5 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100871, China. Electronic address: jiangqk_student@aliyun.com.
PMID: 38972080 DOI: 10.1016/j.ejmech.2024.116646
Abstract

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising Anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.

Keywords

Amino acids; Antitumor; Carbamate prodrugs; Cycloicaritin; Oral bioavailability.

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