The novel pyrimidine and purine derivatives of l-ascorbic acid: synthesis, one- and two-dimensional 1H and 13C NMR study, cytostatic and antiviral evaluation.
The syntheses of the novel C-5 substituted pyrimidine derivatives of l-ascorbic acid containing free hydroxy groups at C-2' (6-10) or C-2' and C-3' (11-15) positions of the lactone ring are described. Debenzylation of the 6-chloro- and 6-(N-pyrrolyl)purine derivatives of 2,3-O,O-dibenzyl-l-ascorbic acid (16 and 17) gave the new compounds containing hydroxy groups at C-2' (18) and C-2' and C-3' (19 and 20). Z- and E-configuration of the C4'C5' double bond and position of the lactone ring of the compounds 6-9 were deduced from their one- and two-dimensional (1)H and (13)C NMR spectra and connectivities in NOESY and HMBC spectra. Compounds 15 and 18 showed the best inhibitory activities of all evaluated compounds in the series. The compound 15 containing 5-(trifluoromethyl)uracil showed marked inhibitory activity against all human malignant cell lines (IC(50): 5.6-12.8 microM) except on human T-lymphocytes. Besides, this compound influenced the cell cycle by increasing the cell population in G2/M phase and induced apoptosis in SW 620 and MiaPaCa-2 cells. The compound 18 containing 6-chloropurine ring expressed the most pronounced inhibitory activities against HeLa (IC(50): 6.8 microM) and MiaPaCa-2 cells (IC(50): 6.5 microM). The compound 20 with 6-(N-pyrrolyl)purine moiety showed the best differential inhibitory effect against MCF-7 cells (IC(50): 35.9 microM).
Gazivoda
Tatjana
T
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Plevnik
Miha
M
Plavec
Janez
J
Kraljević
Sandra
S
Kralj
Marijeta
M
Pavelić
Kresimir
K
Balzarini
Jan
J
De Clercq
Erik
E
Mintas
Mladen
M
Raić-Malić
Silvana
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002247:Carbon Isotopes; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011522:Protons; D011687:Purines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002247:Carbon Isotopes; D011522:Protons; D011687:Purines; D011743:Pyrimidines; C030986:pyrimidine; D001205:Ascorbic Acid; C030985:purine