5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase.
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).
Casanova
Elena
E
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Hernandez
Ana-Isabel
AI
Priego
Eva-María
EM
Liekens
Sandra
S
Camarasa
María-José
MJ
Balzarini
Jan
J
Pérez-Pérez
María-Jesús
MJ
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
C514067:5'-O-tritylinosine; D011684:Purine Nucleosides; D014320:Triphenylmethyl Compounds; D007288:Inosine; D013939:Thymidine Phosphorylase