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1.  Sulfur-Containing 1,3-Dialkylxanthine Derivatives as Selective Antagonists at A1-Adenosine Receptors 
Journal of medicinal chemistry  1989;32(8):1873-1879.
Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [[3H]-N6-(phenylisopropyl) adenosine as radioligand] or striatum [[3H]-5′-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was >740-fold A1 selective.
PMCID: PMC3479653  PMID: 2754711
Biochemical pharmacology  1988;37(19):3653-3661.
Two classes of 8-substituted analogs of theophylline (1,3-dialkylxanthines), having 8-cycloalkyl, 8-cycloalkenyl or 8-(para-substituted aryl) groups, were shown to be potent and, in some cases, receptor subtype selective antagonists at A1- and A2-adenosine receptors. New analogs based on a functionalized cogener approach and on classical medicinal chemical approaches were prepared. Affinity at A1-adenosine receptors was evaluated by inhibition of binding of [3H)N6-phenylisopropyladenosine to rat brain membranes. Activity at A2A-adenosine receptors was measured by the reversal of 5′-N-ethylcarboxamidoadenosine (NECA)-stimulated production of cyclic AMP in membranes from rat pheochromocytoma PC12 cells. Cycloalkenyl analogs containing rigid olefinic bonds differed greatly in potency from the saturated analogs. The selectivity of phenylsulfonamide analogs depended on distal structural features. Novel xanthine analogs include diamino-, thiol-, aldehyde, and halogen-substituted derivatives, peptide conjugates of 8-[4-[2-aminoethylaminocarbonylmethyloxy]phenyl]1,3-dipropylxanthine (XAC), and a hydroxyethylamide analog of XAC.
PMCID: PMC3469272  PMID: 3178879
3.  Inhibition of HIV-1 replication in CD4+ and CD14+ cells purified from HIV-1-infected individuals by the 2-5A agonist immunomodulator, 2-5AN6B 
Two major interferon (IFN)-mediated antiviral defense enzymes are double-stranded (ds)RNA-dependent 2′,5′-oligoadenylate (2-5A) synthetase (2-5OAS) and p68 kinase (PKR). When activated by dsRNA, 2-5OAS synthesizes 2-5A, which binds to and activates RNase L. Activated RNase L hydrolyzes single-stranded viral RNA, thereby inhibiting viral protein synthesis. HIV-1 inhibits the IFN-mediated intracellular antiviral pathways. We have reported the synthesis and characterization of a nuclease-resistant 2-5A agonist (2-5AN6B) that overcomes the HIV-1 induced blockades by restoring the 2-5OAS/RNase L antiviral pathway (Homan, J.W., et al., J Acquir Immune Defic Syndr 2002;30:9–20). The objective of this study was to test the effect of 2-5AN6B on chronically infected CD4+ T lymphocytes and CD14+ monocytes derived from HIV-1 seropositive individuals. Wild type HIV-1 replication was effectively inhibited by 2-5AN6B in CD4+ T lymphocytes and CD14+ monocytes purified from HIV-1 seropositive individuals (n = 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5AN6B and report that 2-5AN6B exerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC90 > 100,000 nM). Furthermore, 2-5AN6B did not alter the cellular RNA profile, affect CCR5 or CXCR4 co-receptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5AN6B, and naturally occurring 2-5A4, act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist, 2-5AN6B, has potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection.
PMCID: PMC1941645  PMID: 17263642
2-5A agonist; HIV-1 replication; 2-5OAS/RNase L antiviral pathway; CD4+ and CD14+ cells; Toll-like receptor

Results 1-3 (3)