title: 5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase.
abstract: On the basis of our previous findings that 5'-O-tritylinosine (KIN59) behaves as an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken the synthesis and enzymatic evaluation of a novel series of nucleoside analogues modified at positions 1, 2, or 6 of the purine ring and at the 5'-position of the ribose moiety of the lead compound KIN59. SAR studies indicate that quite large structural variations can be performed on KIN59 without compromising TPase inhibition. Thus, incorporation of a cyclopropylmethyl or a cyclohexylmethyl group at position N(1) of 5'-O-tritylinosine increases the inhibitory activity against TPase 10-fold compared to KIN59. Moreover, the trityl group at the 5'-position of the ribose seems to be crucial for TPase inhibition. The here reported results further substantiate that 5'-O-trityl nucleosides represent a new class of TPase inhibitors that should be further explored in those biological systems where TPase plays an instrumental role (i.e. angiogenesis).
authors.affiliation: Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Casanova
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Hernandez
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C514067:5'-O-tritylinosine; D011684:Purine Nucleosides; D014320:Triphenylmethyl Compounds; D007288:Inosine; D013939:Thymidine Phosphorylase