Synthesis of pyridazine analogues of the naturally occurring nucleosides cytidine, uridine, deoxycytidine, and deoxyuridine.
The condensation of 4,5-dichloro-3-[(trimethylsilyl)oxy]pyridazine (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (6) was accomplished by the stannic chloride procedure to yield 4,5-dichloro-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyridazin-6-one (7). Procedures used to unequivocally determine the site of ribosylation and anomeric configuration of 7 are discussed. Treatment of 7 with liquid ammonia effected a concomitant removal of the blocking groups and selective nucleophilic displacement of the 4-chloro group. Subsequent dehalogenation yielded 4-amino-1-(beta-D-ribofuranosyl)pyridazin-6-one (11, 6-aza-3-deazacytidine). Treatment of 7 with methanolic sodium methoxide, followed by dehalogenation and hydrolysis with aqueous alkali, yielded 4-hydroxy-1-beta-D-ribofuranosylpyridazin-6-one (6-aza-3-deazauridine, 15). The syntheses of various nucleosides derived from 7, 11, and 15 are described. Condensation of 5 with 3,5-di-O-p-toluoyl-2-deoxy-D-erythro-pentofuranosyl chloride (27) gave a mixture of the blocked anomeric 2'-deoxynucleosides 28 and 29. Nucleoside 28, the beta anomer, was treated in the same manner as 7 to yield 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (32, 6-aza-3-deaza-2'-deoxycytidine) and 4-hydroxy-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (32, 6-aza-3-deaza-2'-deoxycytidine) and 4-hydroxy-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (34, 6-aza-3-deaza-2'-deoxy-uridine). 6-Aza-3-deazauridine (15) was found to inhibit the growth of L1210 cells with an ID50 of about 7 x 10(-5) M.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D003562:Cytidine / Q000031:analogs & derivatives; D003841:Deoxycytidine / Q000031:analogs & derivatives; D003857:Deoxyuridine / Q000031:analogs & derivatives; D006868:Hydrolysis; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D011724:Pyridazines; D011741:Pyrimidine Nucleosides; D003841:Deoxycytidine; D003562:Cytidine; D003857:Deoxyuridine; D014529:Uridine