1,2,4-Diazaphosphole nucleosides. Synthesis, structure, and antitumor activity of nucleosides with a lambda 3 phosphorus atom.
Glycosylation of 1,2,4 lambda 3-diazaphosphole (4) under Lewis acid catalyzed conditions gave 1-alpha-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole (5) as the only product. Ethyl 1,2,4 lambda 3-diazaphosphole-3-carboxylate (10) was synthesized by the cyclocondensation of ethyl (chlorophosphinidene)(trimethylsilyl)acetate (8) with (trimethylsilyl)diazomethane and subsequent desilylation with tetra-n-butylammonium fluoride. Reaction of 10 with methanolic ammonia at 80 degrees C gave 1,2,4 lambda 3-diazaphosphole-3-carboxamide. Glycosylation of 10 using trimethylsilyl triflate catalyst followed by ammonlysis gave the ribavirin (1) analogue 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-carboxamide (11). Acetylation of 11 and subsequent treatment with phosphorus pentasulfide gave 2',3',5'-tri-O-acetyl-1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3- thiocarboxamide (13). Deprotection with methanolic ammonia gave 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-thiocarboxamide (14). Compound 14 gave a 25% increase in life span (ILS) against L1210 in female BDF1 mice. The anomeric configuration and site of glycosylation of 5 and 13 were established by single-crystal X-ray crystallography.
Riley
T A
TA
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Larson
S B
SB
Avery
T L
TL
Finch
R A
RA
Robins
R K
RK
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D001386:Azides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009705:Nucleosides / Q000138:chemical synthesis*; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D001386:Azides; D009705:Nucleosides; D009943:Organophosphorus Compounds; D007168:IMP Dehydrogenase