Synthesis and antiviral and cytostatic evaluations of the new C-5 substituted pyrimidine and furo[2,3-d]pyrimidine 4',5'-didehydro-L-ascorbic acid derivatives.
The novel C-5 alkynyl substituted pyrimidine (1-11) and furo[2,3-d]pyrimidine derivatives (12-22) of l-ascorbic acid were synthesized by coupling of 5-iodouracil-4',5'-didehydro-5',6'-dideoxy-l-ascorbic acid with terminal alkynes by using Sonogashira cross-coupling reaction conditions. The new compounds were evaluated for their cytostatic and antiviral activities. Among all evaluated compounds, the octynyl-substituted uracil derivative of l-ascorbic acid (3) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC50 = 2-12 microM). Pyrimidine derivatives of l-ascorbic acid containing p-substituted phenylacetylene groups (8-11) displayed also a rather pronounced (IC50 = 3-37 microM) inhibitory effect toward all tumor cell lines. From the bicyclic series of compounds, 6-butylfuro[2,3-d]pyrimidine derivative (12) and 6-p-bromophenylfuro[2,3-d]pyrimidine derivative (19) showed the highest cytostatic activity (IC50 = 4.5-20 microM), particularly against malignant leukemia (L1210) and T-lymphocyte (Molt4/C8 and CEM) cells. Compounds 3 and 9 showed specific albeit moderate activity against cytomegalovirus (CMV, Davis strain, EC50 = 1.8 and 3.8 microM, respectively, for compounds 3 and 9) at a approximately 5-fold lower concentration than that required to show cytotoxicity.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Tatjana
T
Gazivoda
Mario
M
Sokcević
Marijeta
M
Kralj
Lidija
L
Suman
Kresimir
K
Pavelić
Erik
E
De Clercq
Graciela
G
Andrei
Robert
R
Snoeck
Jan
J
Balzarini
Mladen
M
Mintas
Silvana
S
Raić-Malić
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C523819:1-(6-(4-bromophenyl)furo(2,3-d)pyrimidin-2-on-3-yl)-2-(2',3'-di-O-benzyl-2'-buten-4'-olidylidene)ethane; C523818:1-(6-butylfuro(2,3-d)pyrimidin-2-on-3-yl)-2-(2',3'-di-O-benzyl-2'-buten-4'-olidylidene)ethane; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011743:Pyrimidines; D011744:Pyrimidinones; D001205:Ascorbic Acid