Synthesis and evaluation of 6-(dibromomethyl)-5-nitropyrimidines as potential antitumor agents.
A series of 2,4,6-trisubstituted-5-nitropyrimidines have been prepared and evaluated for inhibition of proliferation of L1210 and H.Ep.2 cells in vitro. The most potent compound was 6-(dibromomethyl)-2-methoxy-4-morpholino-5-nitropyrimidine (11) (L1210, IC50 = 0.32 microM; H.Ep.2, IC50 = 1.6 microM). Of the 6-substituents incorporated, only CHBr2, CH2Br, and CHO were compatible with antiproliferative activity, while a wider variety of 4-substituents were tolerated. At concentrations near the IC50 for antiproliferative activity, a delayed resumption of cell proliferation in L1210 cultures indicated that the activity of the compounds was short-lived and suggested they might act by an alkylation mechanism.
Thompson
M D
MD
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Cupps
T L
TL
Wise
D S
DS
Wotring
L L
LL
Townsend
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011684:Purine Nucleosides; D011743:Pyrimidines; D012263:Ribonucleosides; C034051:6-methylpurine riboside; C005248:nebularine