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Biomedical subjects

Andreas Link

Publications and source records attributed to Andreas Link.

26 records · Page 2Linked to original sources
PubMed2002

5'-Deoxy congeners of 9-(3-amido-3-deoxy-beta-D-xylofuranosyl)-N(6)-cyclopentyladenine: new adenosine A(1) receptor antagonists and inverse agonists.

The synthesis and structure-activity relationship of N(6)-cyclopentyl-3'-substituted-xylofuranosyladenosine analogues with respect to various adenosine receptors were explored in order to identify selective and potent antagonists and inverse agonists for the adenosine A(1) receptor. In particular, the effects of removal of the 5'-OH group and introduction of selected substituents at the 3'-NH(2) position of 9-(3-amino-3-deoxy-beta-D-xylofuranosyl)-N(6)-cyclopentyladenine were probed. A solid phase-assisted synthetic approach was used to optimize the 3'-amide functionality. In view of the general concern of the presence of a 5'-OH moiety with regard to cellular toxicity, the present study describes 5'-deoxy compounds with reasonable affinity for the human adenosine A(1) receptor. Interestingly, this study shows that optimization of the 3'-"up" amide substituent can substantially compensate for the drop in affinity for the adenosine A(1) receptor, which is generally observed upon removal of the 5'-OH group. The fact that for several 3'-amido-substituted (5'-deoxy)-N(6)-cyclopentyladenosine derivatives, guanosine 5'-triphosphate-induced shifts in K(i) values were significantly lower than 1 implies that these analogues behave as inverse agonists. This is further supported by their 1,3-dipropyl-8-cyclopentylxanthine-like capacity to increase forskolin-induced adenosine cyclic 3',5'-phosphate production.

Animals↗
PubMed2002

[Acute coronary syndrome--better risk stratification by determination of inflammatory parameters?].

BACKGROUND: In the past years coronary atherosclerosis and plaque rupture have been characterized not only as a problem of growth of smooth vascular cells, of activated thrombocytes and coagulation but also of inflammation. PARAMETERS OF INFLAMMATION: Several studies have demonstrated the importance of C-reactive protein as a marker for cardiovascular complications. Also interleukin-6, tumor necrosis factor-alpha and adhesion molecules are discussed as predictors of a poor prognosis in patients with acute coronary syndromes. RISK STRATIFICATION: A positive troponin T test is correlated with an increased rate of early complications; thus, these patients benefit from an aggressive therapy with GP IIb/IIIa receptor antagonists and acute coronary intervention. The C-reactive protein is predictive for late complications such as restenosis, reinfarction and death due to cardiac events; these patients benefit from close controls and from an anti-inflammatory therapy with acetylsalicyclic acid and statins.

C-Reactive Protein↗
PubMed2002

Improving an antitrypanosomal lead applying nucleophilic substitution on a safety catch linker.

In a joint effort with various laboratories we have been aiming at the structure-based design of glycolysis inhibitors as anti-trypanosomal drugs. 2'-Deoxy-2'-(3-methoxybenzamido)-N(6)-(1-naphtylmethyl)adenosine (1a) was thus revealed as a promising lead structure for the development of selective agents against protozoan parasites. Here we describe the polymer-assisted synthesis of novel amido derivatives of the scaffold 2'-amino-2'-deoxy-N(6)-(1-naphtylmethyl)adenosine (5a) we reported recently. This building block synthesized in solution was treated with an excess of polymer-supported carboxylic acids leading to chemoselective, practically quantitative conversion of the amine to the desired analogous amides. The best compound (1h) from this series was obtained after on-bead nucleophilic substitution of the carboxylic acid equivalent attached to the Kenner safety catch linker and exhibited an improved inhibitory effect on T. b. brucei blood stream forms with an IC(50) of 0.85 microM in vitro

Animals↗
PubMed2002

Anti-malarial activity of N(6)-substituted adenosine derivatives. Part I.

The synthesis and biological evaluation of novel N(6)-substituted adenosine derivatives is reported. The first series of compounds was obtained using an established procedure for the nucleophilic substitution of a 1-(6-chloro-purin-9-yl)-beta-D-1-deoxy-ribofuranose with various amines. In addition, attachment of two different amino-functionalised spacer arms at the N(6)-position of adenosine enabled derivatisation by an innovative polymer-assisted protocol. Thus, we were able to prepare three series of substituted derivatives that displayed activity versus the multiresistant Plasmodium falciparum strain Dd2 in cell culture experiments.

Adenosine↗
PubMedDate not supplied

Antimalarial activity of n(6)-substituted adenosine derivatives (part 2).

We have investigated the in vitro antimalarial activity of a new series of adenosine derivatives. The results show that N(6)-(1-naphthylmethyl)-5'-deoxy-5'-(amido)adenosines as well as N(6)-(4-phenylbenzyl)-5'-deoxy-5'-(amido)adenosines display significant activity against the malaria-causing parasites, with the sterically demanding bisubstituted species reported being active in most cases in the low-micromolar range. The novel compounds with unusual substitution pattern were obtained applying an efficient convergent polymer-assisted solution-phase (cPASP) synthesis protocol. Thus, we were able to prepare a series of substituted derivatives in parallel that would have been difficult to synthesize by standard techniques. The scope and limitations of the synthetic methodology are discussed.

Adenosine↗