Structure−Activity Relationships of 7-Deaza-6-benzylthioinosine Analogues as Ligands of<i>Toxoplasma gondii</i>Adenosine Kinase

Kim, Young Ah; Sharon, Ashoke; Chu, Chung K.; Rais, Reem H.; Safarjalani, Omar N. Al; Naguib, Fardos N.M.; Kouni, Mahmoud H. el

doi:10.1021/jm800201s

Cited by 36 publications

(36 citation statements)

References 48 publications

(200 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unstable halogenose 7 is generated from lactol 9 by Appel's chlorination and is immediately used in the displacement reaction. In accordance with literature reports, 22 the protocol 25 utilizing (KOH/TDA-1/ MeCN-THF) provided the β-anomer 8 contaminated with unseparable amounts of R-anomer in an overall yield of up to 40% from 9.…”

Section: Chemistrysupporting

confidence: 88%

6-(Het)aryl-7-Deazapurine Ribonucleosides as Novel Potent Cytostatic Agents

et al. 2009

View full text Add to dashboard Cite

A series of novel 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.

show abstract

Section: Chemistrysupporting

confidence: 88%

6-(Het)aryl-7-Deazapurine Ribonucleosides as Novel Potent Cytostatic Agents

et al. 2009

View full text Add to dashboard Cite

show abstract

“…However, the enzyme can also phosphorylate several 6- and 7-substituted Ado and inosine analogues to their respective 5′-monophosphate derivatives (Al Safarjalani et al, 2003, 2008 and 2010, Darling et al, 1999, el Kouni, 2003 and 2007, el Kouni et al, 1999, Iltzsch et al, 1995, Kim et al, 2008 and 2010, Rais et al, 2005 and Yadav et al, 2004). Thus, TgAK is not strictly specific for Ado.…”

Section: Resultsmentioning

confidence: 99%

“…TgAK does not phosphorylate any of the natural purine nucleosides other than Ado (el Kouni et al, 1999, Iltzsch et al, 1995 and Krug et al, 1989). However, TgAK, unlike human Ado kinase, can phosphorylate various 6-substituted-9-β-D-ribofuranosylpurine analogues to their respective nucleoside 5′-monophosphates (Al Safarjalani et al, 2003, 2008 and 2010, Darling et al, 1999, el Kouni, 2003 and 2007, el Kouni et al, 1999, Iltzsch et al, 1995, Kim et al, 2008 and 2010, Rais et al, 2005 and Yadav et al, 2004). When certain 6-substituted-9-β-D-ribofuranosylpurine analogues are used as subversive substrates they are selectively phosphorylated by TgAK and become toxic only against the parasites but not their host (Al Safarjalani et al, 2008 and 2010, el Kouni, 2003 and 2007, el Kouni et al, 1999, Rais et al, 2005 and Yadav et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

Naguib

Rais

Safarjalani

et al. 2015

Comparative Biochemistry and Physiology Part B: Biochemistry an

Self Cite

View full text Add to dashboard Cite

Toxoplasma gondii has an extraordinarily ability to utilize adenosine (Ado) as the primary source of all necessary purines in this parasite which lacks de novo purine biosynthesis. The activity of T. gondii adenosine kinase (TgAK, EC 2.7.1.20) is responsible for this efficient salvage of Ado in T. gondii. To fully understand this remarkable efficiency of TgAK in the utilization of Ado, complete kinetic parameters of this enzyme are necessary. Initial velocity and product inhibition studies of TgAK demonstrated that the basic mechanism of this enzyme is a hybrid random bi-uni ping-pong uni-bi. Initial velocity studies showed an intersecting pattern, consistent with substrate-enzyme-co-substrate complex formation and a binding pattern indicating that binding of the substrate interferes with the binding of the co-substrate and vice versa. Estimated kinetic parameters were KAdo = 0.002 ± 0.0002 mM, KATP = 0.05 ± 0.008 mM, and Vmax = 920 ± 35 μmol/min/mg protein. Ado exhibited substrate inhibition suggesting the presence of more than one binding site for Ado on the enzyme. ATP relieved substrate inhibition by Ado. Thus, Ado also binds to the ATP binding site. AMP was competitive with ATP, inferring that AMP binds to the same site as ATP. AMP, ADP and ATP were non-competitive with Ado, therefore, none of these nucleotides binds to the Ado binding site. Combining ATP with ADP was additive. Therefore, the binding of either ATP or ADP does not interfere with the binding of the other. It is concluded that for every ATP consumed, TgAK generates three new AMPs. These findings along with the fact that a wide range of nucleoside 5′-mono, di, and triphosphates could substitute for ATP as phosphate donors in this reaction may explain the efficient and central role played by TgAK in the utilization of Ado as the major source from which all other purines can be synthesized in T. gondii.

show abstract

“…The 7-deaza-6-benzylthioinosine analogues inhibited adenosine kinase, which plays an important role in the purine pathways. Some of these compounds shown similar or even better anti-parasitic properties in comparison with pyrimethamine [32,33]. In another study, researchers succeeded in finding inhibitors of T. gondii enoyl reductase, which takes part in fatty acid synthesis [34].…”

Section: Inhibitors Of Gondii Enzymesmentioning

confidence: 99%