Development of antitumor-active Nucleoside Triphosphate Prodrugs

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被用作抗代谢物。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，它们的摄取很大程度上依赖于人类核苷转运体。其次，核苷类似物转化为其最终活性三磷酸盐的代谢过程往往进行得不够充分，导致药物活性较低。该项目侧重于设计一种三磷酸核苷（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。设想的双生物可逆屏蔽原核苷酸既可以通过被动扩散改善细胞摄取，又可以通过直接在细胞内递送NTP绕过所有酶促步骤。因此，肿瘤细胞内活性三磷酸化剂的浓度显著提高可能会带来更好的药物活性。合成后，抗癌TriPPPro-NTP前药的毒理学特征将在体外试验中确定。此外，将进行肿瘤细胞系筛选（NCI面板）和荧光tripppro化合物的细胞摄取研究。本项目的重点是对新制备的化合物进行体内试验。通过这种方式，将在小鼠模型中检测TriPPPro-NTP前药的行为，并将其与常规药物在不同细胞系中的行为进行比较，以确认其抗增殖作用。到目前为止，还没有在tripppro方法的背景下进行过体内研究。所述的策略有望在抗癌化疗中提供巨大的潜力。

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.