5'-O-Tritylinosine and Analogues as Allosteric Inhibitors of Human Thymidine Phosphorylase

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• 作者：Elena Casanova ; Ana-Isabel Herná ; ndez ; Eva-Mar&iacute ; a Priego ; Sandra Liekens ; Mar&iacute ; a-José ; Camarasa ; Jan Balzarini ; Mar&iacute ; a-Jesú ; s Pé ; rez-Pé ; rez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：September 7, 2006
• 年：2006
• 卷：49
• 期：18
• 页码：5562 - 5570
• 全文大小：145K
• 年卷期：v.49,no.18(September 7, 2006)
• ISSN：1520-4804

文摘

On the basis of our previous findings that 5'-O-tritylinosine (KIN59) behaves as an allosteric inhibitor ofthe angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken the synthesis and enzymaticevaluation of a novel series of nucleoside analogues modified at positions 1, 2, or 6 of the purine ring andat the 5'-position of the ribose moiety of the lead compound KIN59. SAR studies indicate that quite largestructural variations can be performed on KIN59 without compromising TPase inhibition. Thus, incorporationof a cyclopropylmethyl or a cyclohexylmethyl group at position N¹ of 5'-O-tritylinosine increases the inhibitoryactivity against TPase 10-fold compared to KIN59. Moreover, the trityl group at the 5'-position of theribose seems to be crucial for TPase inhibition. The here reported results further substantiate that 5'-O-tritylnucleosides represent a new class of TPase inhibitors that should be further explored in those biologicalsystems where TPase plays an instrumental role (i.e. angiogenesis).