The importance of the 4'-hydroxyl hydrogen for the anti-trypanosomal and antiviral properties of (+)-5'-noraristeromycin and two 7-deaza analogues.
(+)-5'-Noraristeromycin (1) has shown significant antiviral activity while its 7-deaza analogue 2 is an antitrypanosomal candidate. To determine the relevance of the 4'-hydroxyl hydrogen in these activities, a derivative of 1 (that is, 3) where the C-4' hydroxyl hydrogen has been replaced by a methyl group has been prepared beginning with palladium (0) mediated coupling of the sodium salt of N6-benzoyladenine (9) and (1S,4R)-4-methoxy-2-cyclopenten-1-yl acetate (5). The synthesis of compound 5 is described from (1S,4R)-1-[(tert-butyldimethylsilyl)oxy]-4-hydroxycyclopent-2-ene (6) in three steps. Analogous preparations of the 7-deaza and 8-aza-7-deaza derivatives of 3 related to 2 (that is, 4 and 12) are also reported. The new derivatives (3, 4, and 12) failed to show improved antiviral activity. Compound 12 was the only derivative with some anti-trypanosomal activity, giving 40% inhibition of growth at 100 microM against bloodstream forms of a Typanosoma brucei brucei isolate in a standard in vitro screen. This study indicated that the C-4'-hydroxyl hydrogen plays a role in the medicinal properties of 1 and 2.
Seley
K L
KL
Department of Chemistry, Auburn University, AL 36849-5312, USA.
Schneller
S W
SW
De Clercq
E
E
Rattendi
D
D
Lane
S
S
Bacchi
C J
CJ
Korba
B
B
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000302:isolation & purification
C114387:4-methoxy-1-(4-aminopyrazolo(3,4-d)pyrimidin-7-yl)cyclopentane-2,3-diol; D000998:Antiviral Agents; D011720:Pyrazoles; D011725:Pyridines; D014344:Trypanocidal Agents; C076829:5'-noraristeromycin; D000241:Adenosine