Combination of l‑Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2‑Targeting Oral Prodrugs

• Published in: Journal of medicinal chemistry 2017-03, Vol.60 (6), p.2552-2561
• Main Authors: Wang, Gang, Chen, Hongxiang, Zhao, Dongyang, Ding, Dawei, Sun, Mengchi, Kou, Longfa, Luo, Cong, Zhang, Dong, Yi, Xiulin, Dong, Jinhua, Wang, Jian, Liu, Xiaohong, He, Zhonggui, Sun, Jin
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacokinetics; Caco-2 Cells; Carnitine - chemistry; Carnitine - metabolism; Carnitine - pharmacokinetics; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - metabolism; Deoxycytidine - pharmacokinetics; HEK293 Cells; Humans; Mice; Molecular Docking Simulation; Organic Cation Transport Proteins - metabolism; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Solute Carrier Family 22 Member 5; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00049

Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages. Because of the high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine. In addition, OCTN2-targeting prodrugs can simultaneously improve the permeability, solubility, and metabolic stability of gemcitabine. In summary, we present the first evidence that OCTN2 can act as a new molecular target for oral prodrug delivery and, importantly, the linkage carbon chain length is a key factor in modifying the affinity of the substrate for OCTN2.