A. Giner-Sorolla, J. Burchenal, C. López
1981
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Abstract
ABSTRACT The first member of the series, N6-hydroxyadenosine (HAPR), exerted an antitumor activity in mouse leukemias and underwent clinical trials. A toxicity was observed, due to enzymatic hydrolysis by adenosine deaminase. 9-β-D-Arabinosyl-N6-hydroxyadenine (ara-HA) had an inhibitory effect in herpes simplex virus type 1 (HSV-1) replication, but it was also toxic. The 6-nitroso purine nucleosides of the ribosyl and arabinosyl series were obtained by oxidation of the corresponding N6-hydroxyadenine (HAP) derivatives. Nitrosation of N6-hydroxyadenine led to the N6-(nitroso)hydroxyamino derivative which, in contrast to its base, was inactive. Nitrosation of 9-3-D-ribofuranosyl-N6-(1-methylhydrazino) or N6-methylaminopurine gave N6-(methylnitroso)adenosine which exerted growth inhibitory activity in mouse leukemia. The use of adenosine deaminase inhibitors, erythro-9(2-hydroxy-3-nonyl)-adenine (EHNA) and 2′-deoxycoformycin (2′-DCF) resulted in an increased antitumor and antiviral activity of the ribosyl and arabinosyl N6-hydroxyadenines, but they were ineffective in blocking the toxic effects in primates. These results prompted the study of new derivatives with substituents at C-2, as it is known that 2-substituted adenosines are resistant to enzymatic attack. In fact, the 2-amino (AHAPR) and 2-fluoro (FHAPR) N6-hydroxyadenosines were less affected by enzymatic hydrolysis than the unsubstituted nucleosides. The N2,N6-dihydroxyaminopurine ribonucleoside (DHAPR) was effective against mouse leukemia and colon 38 tumor. All these N6-hydroxyadenosines had potent anti-HSV-1 activity in vitro. The biological effect of substituents in the nucleosides depends on their structure, being more effective those with N-OH function on the purine nucleus.