Synthesis and antileukemic activity of chymotrypsin-activated derivatives of 3'-amino-2',3'-dideoxycytidine. (Synthetic nucleosides and nucleotides. XXXIII.
3'-Amino-2',3'-dideoxycytidine (8) was directly synthesized from 2'-deoxycytidine. 2',3'-Dideoxy-3'-(N-acyl-L-phenylalanylamino)cytidines (acyl = butoxycarbonyl (9a), acetyl (9b), benzoyl (9c), and n-hexanoyl (9d)) were synthesized as chymotrypsin-activated prodrugs of 8. This N-protection was required for activation by chymotrypsin to 8. In vitro, compound 8 showed high cytotoxic activity against P388 cells, but the prodrugs 9a-d were ineffective. In vivo, however, these prodrugs showed much higher activity than 8 in mice bearing P388 cells.
Kawaguchi
T
T
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
Sakairi
H
H
Kimura
S
S
Yamaguchi
T
T
Saneyoshi
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D002918:Chymotrypsin / Q000493:pharmacokinetics*; D003845:Deoxycytosine Nucleotides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D003845:Deoxycytosine Nucleotides; D016047:Zalcitabine; C039165:3'-amino-2',3'-dideoxycytidine; D002918:Chymotrypsin