Disease relevance of SRI 774

• Synergistic inhibition of leukemia L1210 cell growth in vitro by combinations of 2-fluoroadenine nucleosides and hydroxyurea or 2,3-dihydro-1H-pyrazole[2,3-a]imidazole [1].
• Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells [2].

High impact information on SRI 774

• Inhibition of growth in the presence of selective drug (6-thioguanine or 2-fluoroadenine) of two 6-thioguanine-resistant cell lines, 66cl4 and 44FTO, as well as a 2-fluoroadenine-resistant line, 168FAR, occurred in the presence of other sensitive cells, demonstrating the transfer of drug sensitivity to drug-resistant cells [3].
• Even though these 2-fluoroadenine nucleosides are very poor substrates for adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine potentiated the growth-inhibitory properties of 2-FdAdo but not 2-F-ara-A in a synergistic manner [1].
• PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis [4].
• Interactions between the purine analogue 2-fluoroadenine 9-beta-D-arabinofuranoside (F-ara-A) and the kinase inhibitor UCN-01 have been examined in human leukemia cells (U937 and HL-60) with respect to induction of mitochondrial damage, caspase activation, apoptosis, and loss of clonogenic survival [2].
• The optimum concentrations of 9-beta-D-arabinofuranosyl 2-fluoroadenine and ara-C necessary to achieve significant drug synergism from in vitro studies were between 10 and 20 microM [5].

Biological context of SRI 774

• Glycosylation of 2-fluoroadenine with the appropriate protected thioglycoside derivatives, followed by deprotection and anomer separation, produced the alpha- and beta-anomers of 2',5'-dideoxy-2-fluoroadenosine (1), 2',5'-dideoxy-2,5'-difluoroadenosine (2), and 2'-deoxy-2-fluoroadenosine (3) [6].
• We isolated two mutants resistant to 2-fluoroadenine in which the pur operon and the xpt-pbuX operon are expressed at increased levels in a PurR-independent manner [7].
• Preparation of a fludarabine intermediate via selective alkylation of 2-fluoroadenine [8].

Anatomical context of SRI 774

• The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase [9].

Associations of SRI 774 with other chemical compounds

• The addition of 2-fluoroadenine, a potent competitive inhibitor of methylthioadenosine phosphorylase (Ki = 0.43 microM) to adenine phosphoribosyl-transferase-deficient cells resulted in a progressive accumulation of 5'-methylthioadenosine in the culture medium, and up to an 85% decrease in adenine production at non-toxic concentrations [10].

References