2-deoxyribose-1-phosphate--(alpha-d-erythro)-isomer and Neoplasms

2-Deoxy-α-d-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported.

Topics: Amides; Anti-HIV Agents; Antineoplastic Agents; Carbasugars; Cell Line, Tumor; HIV; HIV Infections; Humans; Neoplasms; Phosphoric Acids; Prodrugs; Ribosemonophosphates

Thymidine phosphorylase (TP) catalyzes the phosphorolytic cleavage of thymidine (TdR) to thymine and deoxyribose-1-phosphate (dR-1-P). TP, which is overexpressed in a wide variety of solid tumors, is involved in the activation and inactivation of fluoropyrimidines. We investigated the role of TP in 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5FU) and trifluorothymidine (TFT) sensitivity. TP had no effect on TFT while it activated 5'DFUR and to a lesser extent 5FU. In order to provide an explanation for this difference in activation of 5'DFUR and 5FU, we studied the role of the 5FU co-substrate, dR-1-P, needed for its activation.

Topics: Antimetabolites, Antineoplastic; Cell Line, Tumor; Dose-Response Relationship, Drug; Fluorouracil; Humans; Inhibitory Concentration 50; Neoplasms; Pyrimidines; Ribosemonophosphates; Thymidine Phosphorylase; Time Factors; Transfection

The metabolism of 5-fluorouracil (5-FU) in tumors and normal tissues of humans was investigated in vitro. Phosphorylation of 5-FU was faster in tumor tissues than in normal tissues. Phosphorylating activity with 2-deoxy-alpha-D-ribose 1-phosphate (dRiblP) and ATP as cofactors was more active than that with alpha D-ribose 1-phosphate (RiblP) and ATP, or 5-phospho-alpha-D-ribosyldiphosphate (PPRibP) as cofactors. Phosphorylating activity in squamous cell carcinoma of the lung was similar to that in adenocarcinomas. Degradation of 5-FU was much faster in the liver than in other tissues including tumor tissues.

Topics: Adenocarcinoma; Adenosine Triphosphate; Carcinoma, Squamous Cell; Digestive System; Fluorouracil; Gastrointestinal Neoplasms; Humans; Liver; Lung; Lung Neoplasms; Neoplasms; Phosphoribosyl Pyrophosphate; Phosphorylation; Ribosemonophosphates