Modified 5-fluorouracil: Uridine phosphorylase inhibitor
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CTURE OF MACROMOLECULAR COMPOUNDS
Modified 5-Fluorouracil: Uridine Phosphorylase Inhibitor A. A. Lashkova,*, A. A. Shchekotikhinb, A. A. Shtilc, S. E. Sotnichenkoa, and A. M. Mikhailova aShubnikov
Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”, Russian Academy of Sciences, Leninskii pr. 59, Moscow, 119333 Russia b Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, ul. Bol’shaya Pirogovskaya 11, Moscow, 119021 Russia c Blokhin Russian Cancer Research Center, Kashirskoe sh. 23, Moscow, 115478 Russia *e-mail: [email protected] Received February 26, 2016
Abstract—5-Fluorouracil (5-FU) is a medication widely used in chemotherapy to treat various types of cancer. Being a substrate for the reverse reaction catalyzed by uridine phosphorylase (UPase), 5-FU serves as a promising prototype molecule (molecular scaffold) for the design of a selective UPase inhibitor that enhances the antitumor activity of 5-FU and exhibits intrinsic cytostatic effects on cancer cells. The chemical formula of the new compound, which binds to the uracil-binding site and, in the presence of a phosphate anion, to the phosphate-binding site of UPase, is proposed and investigated by molecular simulation methods. DOI: 10.1134/S1063774516050138
INTRODUCTION Currently, cancers are considered an acute problem. More than 10 million new cancer cases are diagnosed and more than 8 million cancer-related deaths occur annually [1]. 5-Fluorouracil (5-FU) is a chemotherapy drug extensively used in the treatment of skin cancer, colon and rectal cancer, breast, gastric, pancreas, ovarian, and bladder cancers, and endometrial carcinoma. Since the enzyme uridine phosphorylase (UPase) exhibits high activity in cancer cells [2–6], high concentrations of the drug (5-FU) are required for effective cancer treatment. An increase in the 5-FU concentration in the blood and tissues of the patient body leads to liver dysfunction, myocardial ischemia, hemorrhage, anemia, leukopenia, and thrombocytopenia and to an enhancement of other side effects. It was shown [7] that UPase inhibitors (for example, 2,2'anhydro-5-ethyluridine) mediate the enhancement of activity of 5-FU as a chemotherapy drug. Owing to the highly conserved structure of the binding sites comprising the active site of prokaryotic and eukaryotic UPases, the properties of their inhibitors can be studied using widely available bacterial UPases (for example, UPase from Salmonella typhimurium (StUPh) [8, 9]) instead of human UPase [10]. The applied UPase inhibitors (for example, 5-benzylacyclouridine) are characterized by low bioavailability; i.e., the transport of inhibitor molecules across cellular membranes is hindered. In addition, all inhibitors studied earlier block only one of the two binding sites: either the nucleoside-binding site [11–14] (for
example, 2.2'-anhydrouridines, 2.3'-anhydrouridines, acyclouridines) or the phosphate-binding site (for example, phosphanes [15]). Being a substrate for the reverse reaction, 5-FU binds to
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