کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10583691 | 981298 | 2014 | 29 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380 Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380](/preview/png/10583691.png)
چکیده انگلیسی
Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150-300Â mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 19, 1 October 2014, Pages 5234-5240
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 19, 1 October 2014, Pages 5234-5240
نویسندگان
Shuhong Wu, Li Wang, Xiao Huang, Mengru Cao, Jing Hu, Hongyu Li, Hui Zhang, Xiaoping Sun, Qing H. Meng, Wayne L. Hofstetter, Jack A. Roth, Stephen G. Swisher, Bingliang Fang,