Synthesis and antitumor activities of novel pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-L-ascorbic acid and 4,5-didehydro-5,6- dideoxy-L-ascorbic acid.
The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascorbic acid (14-17) with free C-2' and C-3' hydroxy groups in the lactone ring were obtained by debenzylation of 11-13 with boron trichloride. Z-Configuration of the C4'=C5' double bond and position of the benzyl group in the lactone ring of 14 were deduced from their (1)H and (13)C NMR spectra and connectivities in COSY, ROESY, and HMBC spectra. The exact stereostructure of 13 was confirmed by its X-ray crystal structure analysis. Of all the compounds in the series, compound 16 containing a 5-fluoro-substituted uracil ring showed the most significant antitumor activities against murine leukemia L1210/0 (IC(50) = 1.4 microg/mL), murine mammary carcinoma FM3A/0 (IC(50) = 0.78 microg/mL), and, to a lesser extent, human T-lymphocyte cells Molt4/C8 (IC(50) = 31.8 microg/mL) and CEM/0 cell lines (IC(50) = 20.9 microg/mL).
Raić-Malić
S
S
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Laboratory of General and Inorganic Chemistry, University of Zagreb, Croatia. Silvana.Raic@pierre.fkit.hr
Svedruzić
D
D
Gazivoda
T
T
Marunović
A
A
Hergold-Brundić
A
A
Nagl
A
A
Balzarini
J
J
De Clercq
E
E
Mintas
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C418114:1-(2,4-dioxo-5-fluoro-(1H,3H)-pyrimidin-1-yl)-2-(2,3-dihydroxy-2-buten-4-olidylidene)ethane; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011743:Pyrimidines; D001205:Ascorbic Acid; D005472:Fluorouracil