6- Aminonucleosides

Aufier dem Aminonucleosid II wurden Verbindungen mit analoger Struktur synthetisiert, die an Stelle der 3-Amino-D-ribose 3-Amino-D-arabinose (12) oder N-Acetyl-D-glucosamin (9) enthalten. 

The antagonistic properties of FR 900452 have also been examined in a model of endotoxin shock, the haemodynamic and haematological manifestations of this condition closely resembling the changes induced by PAF. FR 900452 (10 mg/kg, i.v.) almost completely prevents PAF (1 /ig/kg, i.v.)-induced thrombocytopenia and leukocytopenia in rabbits [295]. It also significantly inhibits endotoxin (E. coli LPS, 30 /ig/kg, i.v.)-induced thrombocytopenia but not leukocytopenia. The same dose of FR 900452 also causes the decreased arterial blood pressure to return to normal in the endotoxin-induced rat hypotension model, an effect also reported for other PAF inhibitors [121, 274], Finally, FR 900452 has been tested for its therapeutic effect on rat nephrosis induced by aminonucleoside (puromycin, 100 mg/kg, i.p.). At 100 mg/kg twice a day orally for 6 days, the agent significantly reduces urinary protein loss in nephrotic rats [298]. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Administration of 3 -amino-3 -deoxy-A,ALdimethyladenosine (the amino-nucleoside of puromycin) to rats produces a nephrotic syndrome that is clinically indistinguishable from the nephrotic syndrome of unknown origin frequently observed in children [365]. Rats, monkeys, and humans are susceptible to this nephrotoxicity and susceptibility has been related to specie ability to demethylate the aminonucleoside [213]. 7V -Methyladenosine prevents development of this syndrome [365a]. 

Although inferior to pyrimethamine plus sulphonamides, both puromycin and the aminonucleoside are active against Toxoplasma gondii in vivo [403]. These drugs are also effective against Endamoeba histolytica in vitro [404], and puromycin is active against the infection in man [405]. 

The mechanism of inhibition of these protozoal infections by the most active drugs, puromycin and the aminonucleoside, is not known. Puromycin and nucleocidin both interfere with protein synthesis, but the aminonucleoside does not. It is known to be demethylated to 3 -amino-3-deoxyadenosine, which is phosphorylated and interferes with nucleic acid metabolism (see above). Whether puromycin must be converted to the aminonucleoside before it can inhibit protozoa has not been established. Some purine analogues known to interfere with nucleic acid metabolism, however, are less effective as antiprotozoal agents, even in vitro, perhaps because their effects are primarily on the de novo pathway which many, if not all, protozoa do not use [406]. 

Pedraza-Chaverri, J. et ah, Garlic ameliorates hyperlipidemia in chronic aminonucleoside nephrosis, Mol. Cell. Biochem., 211, 69-77, 2000b. 

C4. Caulfield, J. P., and Farquhar, M. G., Loss of anionic sites from the glomerular basement membrane in aminonucleoside nephrosis. Lab. Invest. 39, 505-512 (1978). 

Finco DR (1997) Kidney function. In Kaneko JJ, Harvey JW, Brass ML (eds) Clinical Biochemistry of Domestic Animals, 6th edn. Academic Press, San Diego, pp 441-485 Finn WF, Porter GA (1998) Urinary biomarkers and nephrotoxicity. In DeBroe ME, Porter GA, Bennett WM, Verpooten GA (eds) Clinical Nephrotoxins. Kluwer Academic Publishers, Dordrecht, Netherlands, pp 61-99 Gherardi E, Calandra S (1982) Plasma and urinary lipids and lipoproteins during the development of nephrotic syndrome induced in the rat by puromycin aminonucleoside. Biochim Biophys Acta 710 188-196 Graff L (1983) A Handbook of Routine Urinalysis. JB Lippin-cott Company, Philadelphia... 

Asami T, Toyabe S, Uchiyama M (1999) Effects of glutathione on aminonucleoside nephrosis in rats. Acta Med Biol 47 9-14... 

Guoji Y, Orita M, Tashiro K, Abe H (1994) Effects of gly-cyrrhetinic acid on aminonucleoside nephrosis in rats. Naunyn-Schmiedeberg s Arch Pharmacol 349 318-323 Kimura M, Takahashi H, Ohtake Tet al. (1993) Interstrain differences in murine daunomycin-induced nephrosis. Nephron 63 193-198... 

Nosaka K, Takahashi T, Nishi T et al. (1997) An adenosine deaminase inhibitor prevents puromycin aminonucleoside nephrotoxicity. Free Rad Biol Med 22 597-605 Park Y-S, Guijarro C, Kim Y et al. (1998) Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats. Am J Kidney Dis 31 190-194... 

Pedraza-Chaverri J, Granados-Silvestre MA, Medina-Campos ON, Hernandez-Pando R (1999) Effect of the in vivo catalase inhibition on aminonucleoside nephrosis. Free Rad Biol Med 27 245-253... 

Yayama K, Kawao M, Tujii H et aL (1993) Dup 753 prevents the development of puromycin aminonucleoside-induced nephrosis. Eur J Pharmacol 236 337-338 Yoneda H, Toriumi W, Ohmachi Y et al. (1998) Involvement of angiotensinll in development of spontaneous nephrosis in Dahl salt-sensitive rats. Eur J Pharmacol 362 213-219... 

Immune complexes Aminoglycoside antibiotics Puromycin aminonucleoside Adriamycin Penicillamine... 

Moreover, this chemoenzymatic process yields new aminonucleosides that are very difficult to prepare by chemical procedures alone [15). Scheme 10.3 shows a general chemoenzymatic procedure for obtaining 3 -amino-xylo-nucleosides. The key step is based on the 5 -directed intramolecular nucleophiUc substitution at the 3 -activated position of the nucleoside. This methodology is applicable to ribonu-cleosides and 2 -deoxyribonucleosides and shows the utility of a combination of... 

Aminonucleosides can offer interesting physiological properties. Some routes for the synthesis of new analogs of this kind of compounds have been described [26] A modified route for the preparation of 3, 5 -diamino-3",5 -trideoxythymidine is outlined in Scheme 10.10. The reaction, which takes place in four steps with an overall yield of 63%, is an improvement on the earlier described process [27]. 

CouTSOGEORGOPOULOS, C., Amino acyl-aminonucleoside inhibitors of protein synthesis. The effects of amino acyl ribonucleic add on the inhibition. Biochemistry 1967, 6, 1704-1711. 

AMINO-5-NITROTHIAZOLE see ALQOOO AMINONITROTHIAZOLUM see ALQOOO 2-AMINO-4-NITROTOLUENE see NMP500 AMINONUCLEOSIDE see ALQ625 AMINONUCLEOSIDE PUROiMYCIN see ALQ625 4-AMINO-N> -METHYLPTEROYLGLUTAMIC ACID see MDV500... 

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