75763-51-8Relevant academic research and scientific papers
Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of trypanosomatidae via structure-based drug design
Bressi,Verlinde,Aronov,Shaw,Shin,Nguyen,Suresh,Buckner,van Voorhis,Kuntz,Hol,Gelb
, p. 2080 - 2093 (2007/10/03)
In our continuation of the structure-based design of anti-trypanosomatid drugs, parasiteselective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N6-(1-naphthalenemethyl)-2′-deoxy-2′- (3-methoxybenzamido)adenosine (6e), N6-(substituted-naphthalenemethyl)-2′-deoxy-2′- (substituted-benzamido)adenosine analogues were investigated. N6(1 -Naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (6m), N6- [1-(3-hydroxynaphthalene)methyl]-2′-deoxy-2′- (3,5-dimethoxybenzamido)adenosine (7m), N6-[1-(3-methoxynaphthalene)methyl]-2′-deoxy-2′- (3,5-dimethoxybenzamido)adenosine (9m), N6-(2-naphthalenemethyl)-2′-deoxy-2′1- (3-methoxybenzamido)adenosine (11e), and N6-(2-naphthalenemethyl)-2′deoxy-2′- (3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50'S of these compounds were in the range 2-12 μM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure- activity relationships of this class of compounds, a library of 240 N6-(substituted)-2′-deoxy-2′-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2′ substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5′-amido substituents and found that 2′,5′-dideoxy-2′-(3,5-dimethoxybenzamido)-5′- (diphenylacetamido)adenosine (49) displays an IC50 of 60-100 μM against the three parasite GAPDH's.
Microbial Synthesis of Purine 2'-Amino-2'-deoxyribosides
Utagawa, Takashi,Mirisawa, Hirokazu,Yamanaka, Shigeru,Yamazaki, Akihiro,Hirose, Yoshio
, p. 2711 - 2718 (2007/10/02)
The microbial synthesis of some purine 2'-amino-2'-deoxyribonucleosides from purine bases and 2'-amino-2'-deoxyuridine is described.Various bacteria, especially Erwinia herbicola, Salmonella schottmuelleri, Enterobacter aerogenes and Escherichia coli, were able to transfer the aminoribosyl moiety of 2'-amino-2'-deoxyuridine to purine bases (transaminoribosylation) in the presence of inorganic phosphate.The optimum conditions for the reaction were pH 7.0 and 63 deg C.No reaction was observed in the abscence of inorganioc phosphate and the optimum concentration of it was around 30 mM.Adenine, guanine, 2-chlorohypoxanthine and hypoxanthine were transformed to the corresponding 2'-amino-2'-deoxyribonucleosides by the catalytic activity of the wet cell paste of Enterobacter aerogenes AJ 11125.The enzymatically synthesized purine 2'-amino-2'-deoyxyribonucleosides were isolated and identified by physicochemical means. 2'-Amino-2'-deoxyadenosine strongly inhibited the growth of Hela cells in theis tissue culture, and the ED50 was 2.5 μg/ml.
