Nucleic acid related compounds. 74. Synthesis and biological activity of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues that function as mechanism-based inhibitors of S-adenosyl-L-homocysteine hydrolase and/or ribonucleotide reductase.
Treatment of 2-amino-6-chloro-9-(beta-D-ribofuranosyl)purine (21) with TBDMS chloride/imidazole/DMF gave a separable mixture of 5'-O, 2',5'-bis-O (22), 3',5'-bis-O (23), and 2',3',5'-tris-O-TBDMS derivatives. Oxidation of 22 and 23 with CrO3/pyridine/Ac2O, treatment of the respective ketonucleosides with methylenetriphenylphosphorane, and deprotection gave 2-amino-6-chloro-9-[3(and 2)-deoxy-3(and 2)-methylene- beta-D-erythro-pentofuranosyl]purines (28 and 37) that were converted into other 2-amino-6-substituted-purine analogues. Tubercidin was converted into 2'-deoxy-2'-methylenetubercidin (49) by an analogous route. Inactivation of S-adenosyl-L-homocysteine hydrolase by 2'- and 3'-methyleneadenosine analogues was investigated. Mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase and anticancer and antiviral activities of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues are discussed.
Robins
M J
MJ
Department of Chemistry, Brigham Young University, Provo, Utah 84602.
Samano
V
V
Zhang
W
W
Balzarini
J
J
De Clercq
E
E
Borchardt
R T
RT
Lee
Y
Y
Yuan
C S
CS
D043383:Adenosylhomocysteinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D003839:Deoxyadenosines; D009705:Nucleosides; D003841:Deoxycytidine; C075260:2'-deoxy-2'-methyleneadenosine; C075259:2'-deoxy-2'-methyleneguanosine; D012264:Ribonucleotide Reductases; D006867:Hydrolases; D043383:Adenosylhomocysteinase; C056034:2'-deoxy-2'-methylenecytidine; D003849:Deoxyguanosine