Synthesis and Evaluation of Multisubstrate Bicyclic Pyrimidine Nucleoside Inhibitors of Human Thymidine Phosphorylase

Abstract

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.

2′‐Deoxy‐2′‐α‐C‐(hydroxymethyl)adenosine as Potential anti‐HCV Agent

“…Because ozonolysis is not practical when larger amounts of material are needed, we tried to cleave the double bond by LemieuxJohnson oxidation using OsO 4 , N-methylmorpholine N-oxide (NMMO) and NaIO 4 followed by in situ reduction using NaBH 4 . [23][24][25] In our case, the conversion of the phenylethenyl group of compound 17 into the hydroxymethyl group was not very efficient following this procedure (10 %). To increase the yield of the reaction, the co-oxidant NMMO was replaced by K 3 Fe(CN) 6 /K 2 CO 3 , which was identified to be a better co-oxidant system by Minato et al [26] and the two oxidation steps were carried out separately by isolating the dihydroxy compound 18.…”

Multisubstrate adduct inhibitors: Drug design and biological tools

“…The substitution to 54c rendered the compound inactive. For both types of analog, the endo-isomer was 30-60 times more active than the exo-compound but less active than 54a 128 . First, the bisubstrate 57 was kinetically evaluated using the membrane-bound form of fucosyltransferase.…”

“…TPase catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose 1-phosphate 126 . 128,129 . These compounds were evaluated as inhibitors of human recombinant TPase (Table 8).…”

Syntheses of 1-[2-(Phosphonomethoxy)Alkyl]Thymine Monophosphates and an Evaluation of their Inhibitory Activity Toward Human Thymidine Phosphorylase

“…In particular, we have a hope that a potential multipoint interaction of these monophosphates to the human enzyme could further depend on the substitution and chirality of the alkyl chains. [26][27][28]30] For the preparation of compounds 4a-d, we have chosen the chemical phosphorylation (see Experimental). It is known that a number of phosphorylated ANPs play an important role in biological processes.…”