Design of Novel Potent Inhibitors of Human Uridine Phosphorylase-1: Synthesis, Inhibition Studies, Thermodynamics, and in Vitro Influence on 5‑Fluorouracil Cytotoxicity

Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Sel...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8892-8902
Main Authors: Renck, Daiana, Machado, Pablo, Souto, Andre A, Rosado, Leonardo A, Erig, Thais, Campos, Maria M, Farias, Caroline B, Roesler, Rafael, Timmers, Luis F. S. M, de Souza, Osmar N, Santos, Diogenes S, Basso, Luiz A
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Cell Survival - drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fluorouracil - chemical synthesis
Fluorouracil - chemistry
Fluorouracil - pharmacology
HT29 Cells
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Thermodynamics
Uridine Phosphorylase - antagonists & inhibitors
Uridine Phosphorylase - metabolism
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Summary:Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors of human uridine phosphorylase (hUP) have been proposed as a strategy to increase Urd levels. We describe synthesis and characterization of a new class of ligands that inhibit hUP type 1 (hUP1). The design of ligands was based on a possible SN1 catalytic mechanism and as mimics of the carbocation in the transition state of hUP1. The kinetic and thermodynamic profiles showed that the ligands here presented are the most potent in vitro hUP1 inhibitors developed to date. In addition, a lead compound improved the antiproliferative effects of 5-FU on colon cancer cells, accompanied by a reduction of in vitro 5-FU cytotoxicity in aggressive SW-620 cancer cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401389u