Project Details
Projekt
Development of antitumor-active Nucleoside Triphosphate Prodrugs
Subject Area
Pharmacy
Biological and Biomimetic Chemistry
Hematology, Oncology
Biological and Biomimetic Chemistry
Hematology, Oncology
Term
from 2018 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401301271
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.
DFG Programme
Research Grants
