Development of antitumor-active Nucleoside Triphosphate Prodrugs

抗肿瘤活性核苷三磷酸前药的开发

• 批准号: 401301271
• 负责人: Professor Dr. Chris Meier
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/401301271?language=en
• 关键词: Development; antitumor; active; Nucleoside; Triphosphate

Due to the lack of potent drugs a variety of different types of cancer represent a global threat to human health. As a known class of classical drugs, nucleoside analogues are used as antimetabolites in chemotherapy. However, the efficiency of these nucleoside analogues is limited by various cellular barriers. First, their uptake is largely dependent on human nucleoside transporters. Second, the metabolic conversion of nucleoside analogues into their ultimately active triphosphates often proceeds insufficiently resulting in a low activity of the drug. This project focuses on the design of a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach) applied to approved anti-cancer antimetabolites like Gemcitabine and fluorouracil. Such a concept was recently successful in the arena of antivirally active nucleoside analogues. The envisaged double bioreversible masked pronucleotides enable both an improved cellular uptake by passive diffusion as well as a bypass of all enzymatic steps by the direct intracellular delivery of the NTP. Therefore, a significant higher concentration of the active triphosphorylated agent inside tumor cells may be accomplished with the consequence of a better drug activity. After synthesis, a toxicological profile of the anti-cancer TriPPPro-NTP prodrugs will be determined in in vitro tests. In addition, a tumor cell line screening (NCI panel) and cellular uptake studies with a fluorescent TriPPPro-compound will be performed. Of key interest of this project are in vivo test of the newly prepared compounds. In this manner, the behavior of TriPPPro-NTP prodrugs will be examined and compared to their conventional drugs in different cells lines in mouse models to confirm an anti-proliferative effect. So far, in-vivo studies have never been conducted in the context of the TriPPPro-approach. The described strategy will hopefully offer high potential to be used in anti-cancer chemotherapy.

由于缺乏有效的药物，各种不同类型的癌症对人类健康构成了全球性威胁。作为一类已知的经典药物，核苷类似物在化疗中用作抗代谢药。然而，这些核苷类似物的效率受到各种细胞屏障的限制。首先，它们的吸收很大程度上依赖于人类核苷转运蛋白。其次，核苷类似物代谢转化为其最终活性三磷酸通常进展不充分，导致药物活性低。该项目的重点是设计核苷三磷酸 (NTP) 递送系统（TriPPPro 方法），应用于已批准的抗癌抗代谢药物，如吉西他滨和氟尿嘧啶。这种概念最近在抗病毒活性核苷类似物领域取得了成功。设想的双生物可逆掩蔽前核苷酸既能够通过被动扩散改善细胞摄取，又能够通过直接细胞内递送 NTP 绕过所有酶促步骤。因此，肿瘤细胞内活性三磷酸化试剂的浓度显着升高，从而具有更好的药物活性。合成后，抗癌 TriPPPro-NTP 前药的毒理学特征将在体外测试中确定。此外，还将进行肿瘤细胞系筛选（NCI panel）和使用荧光 TriPPPro 化合物的细胞摄取研究。该项目的主要兴趣是新制备的化合物的体内测试。通过这种方式，将在小鼠模型的不同细胞系中检查 TriPPPro-NTP 前药的行为并与其常规药物进行比较，以确认其抗增殖作用。迄今为止，尚未在 TriPPPro 方法的背景下进行过体内研究。所描述的策略有望在抗癌化疗中具有很高的应用潜力。