title: Design of novel potent inhibitors of human uridine phosphorylase-1: synthesis, inhibition studies, thermodynamics, and in vitro influence on 5-fluorouracil cytotoxicity.
abstract: 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.
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) , 6681/92-A, TecnoPuc, Av. Ipiranga, 90619-900 Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Daiana
authors.initials: D
authors.lastname: Renck
authors.forename: Pablo
authors.initials: P
authors.lastname: Machado
authors.forename: Andre A
authors.initials: AA
authors.lastname: Souto
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Rosado
authors.forename: Thais
authors.initials: T
authors.lastname: Erig
authors.forename: Maria M
authors.initials: MM
authors.lastname: Campos
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Farias
authors.forename: Rafael
authors.initials: R
authors.lastname: Roesler
authors.forename: Luis F S M
authors.initials: LF
authors.lastname: Timmers
authors.forename: Osmar N
authors.initials: ON
authors.lastname: de Souza
authors.forename: Diogenes S
authors.initials: DS
authors.lastname: Santos
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Basso
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005472:Fluorouracil / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014543:Uridine Phosphorylase; D005472:Fluorouracil