Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides.
Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.
Manfredini
S
S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Bazzanini
R
R
Baraldi
P G
PG
Guarneri
M
M
Simoni
D
D
Marongiu
M E
ME
Pani
A
A
Tramontano
E
E
La Colla
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003500:Cyclization; D004770:Enterovirus / Q000187:drug effects; D006031:Glycosylation; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D017646:Organosilicon Compounds; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D012825:Silicon; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014709:Vero Cells
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009705:Nucleosides; D017646:Organosilicon Compounds; D011720:Pyrazoles; C024548:hexamethylsilazane; D012825:Silicon