13389-13-4

Upstream product

• 2946-39-6 8-bromoadenosine 
• 3001-45-4 8-mercaptoadenosine 
• 34408-14-5 8-chloroadenosine 
• 74-89-5 methylamine 

Relevant academic research and scientific papers

Synthesis of Some 1-Methyladenine Analogs and Their Biological Activities on Starfish Oocyte Maturation

Starfish oocytes are naturally arrested at the prophase stage of the first meiotic division and resume meiosis in response to the maturation-inducing hormone 1-methyladenine. Five analogs of 1-methyladenine including three novel ones were synthesized and tested for biological activities as 1-methyladenine agonists or antagonists in triggering reinitiation of meiosis of starfish Asterina pectinifera oocytes, as well as for competition in binding to putative 1-methyladenine receptors with respect to 1-methyladenine. 1-Ethyladenine was an effective agonist, but 1-propyladenine served as a weak antagonist to 1-methyladenine, indicating strict specificity for a relatively small N-1 substituent. Analogs in which carboxymethyl or methyl group substitutes for a hydrogen of 6-amino group still retained oocyte maturation-inducing activity, but to a much lesser degree. The results of the competitive binding assay with cortices of oocytes demonstrated that these agonists or antagonist inhibited the binding of [3H] 1-methyladenine to receptors. 8-methylamino-1-methyladenine competed only weakly with [3H] 1-methyladenine for the binding to cortices, although it behaved as a potent antagonist.

Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors

ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.

Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors

Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 ± 3.8 μM), and subsequent structure-activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 ± 0.19 μM). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity.

New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C8-substituted adenine analogues bound in the active site.

Anti-HCV nucleoside derivatives

The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.

SYSTEMATIC SYNTHESIS OF PURINE 8,5'-IMINO AND SUBSTITUTED IMINO CYCLONUCLEOSIDES

A systematic synthesis of some purine 8,5'-imino and substituted imino cyclonucleosides has been introduced.Thus, 2',3'-O-isopropylidene derivatives of 8-methylaminoadenosine, 8-methylaminoinosine, 8-benzylaminoadenosine and 8-benzylaminoinosine with exce