Sulfamide antifolates inhibiting thymidylate synthase: synthesis, enzyme inhibition and cytotoxicity.

Abstract

Synthesis and biological evaluation are described of seven new analogues (3-9) of two potent thymidylate synthase inhibitors, 10-propargyl-5,8-dideazafolate (1) and its 2-methyl-2-deamino congener ICI 198583 (2). While the new compunds 3 and 4 were analogues of 1 and 2, respectively, containing a p-aminobenzenesulfonyl residue in place of the p-aminobenzoic acid residue, the remaining 5 new compounds were analogues of 4 with the L-glutamic acid residue replaced by glycine (5), L-valine (6), L-alanine (7), L-phenylglycine (8) or L-norvaline (9). The new analogues were tested as inhibitors of thymidylate synthases isolated from tumour (Ehrlich carcinoma), parasite (Hymenolepis diminuta) and normal tissue (regenerating rat liver) and found to be weaker inhibitors than the parent 10-propargyl-5,8-dideazafolic acid. Selected new analogues, tested as inhibitors of growth of mouse leukemia L 5178Y cells, were less potent than the parent 10-propargyl-5,8-dideazafolic acid. Substitution of the glutamyl residue in compound 4 with L-norvaline (9) resulted in only a 5-fold stronger thymidylate synthase inhibitor, but a 40-fold weaker cell growth inhibitor.Thymidylate synthase (EC 2.1.1.45) catalyzes the C(5) methylation of 2¢-deoxyuridylate (dUMP) in a concerted transfer and reduction of the one-carbon group (at the alde-hyde oxidation level) of N 5 , 10 -methylenetetrahydrofolate, and with concomitant production of dihydrofolate and thymidylate. The in vivo folate cofactor and the product of the Vol. 49 No. 2/2002 407-420 QUARTERLY * Preliminary reports were presented at the 10th Int. Abbreviations: DMA, dimethylacetamide; DMF, dimethylformamide; LSIMS, liquid secondary ion spectroscopy; mp, melting point. b CH(CH 3 ) 2 ), 3.31 (t, J = 2.4 Hz, 1H, CºCH), 4.36 (d, J = 6.0 Hz, 2H, CH 2 CºC), 3.65 (m, 1H, Val a CH), 4.20 (s, 2H, ArCH 2 N<), 6.87 (d, J = 8.7 Hz, 2H, Ph: 3¢-H and 5¢-H), 7.76 (d, J = 8.7 Hz, 2H, Ph: 2¢-H and 6¢-H), 7.18 (d, J = 8.8 Hz, 1H, quinazoline 8-H), 7.48 (dd, J = 9.0, 1.5 Hz, 1H quinazoline 7-H), 7.78 (s,

Nutritional and Hygienic Quality of Raw Milk in the Mid-Northern Region of Algeria: Correlations and Risk Factors

“…However, high levels of bacteria in raw milk can affect the quality and shelf life of milk even if it is pasteurized [ 4 , 5 ]. The presence of antibiotic residues in milk can sometimes be a danger to the consumer, triggering in rare cases allergy problems [ 6 ] and toxic accidents [ 7 , 8 ] or still favoring the emergence of resistant microflora, especially being a major cause of disruptions in fermentation and maturation of dairywide consumption. Many works have been done on the qualities of raw milk at different levels of the dairy sector in Algeria.…”

Survey on the presence of antibiotic residues in raw milk samples from six sites of the dairy pool of Niamey, Niger

“…Residues in food from animal origin can constitute a risk for the consumer by initiating the following side effects: Allergic outcomes (penicillin and streptomycin), poisoning (chloramphenicol), modification of the intestinal flora (tetracycline), and selection of antibiotic-resistant bacteria [2,3].…”

Efficient Synthesis of Non-Natural l-2-Aryl-Amino Acids by a Chemoenzymatic Route

“…Enantiopure non-natural 2-aryl-amino acids have been utilized as important building blocks or starting materials for the production of pharmaceuticals . For instance, l -phenylglycine and its derivatives are important intermediates for synthesizing proctolin analogues and HIV protease inhibitor or paclitaxel . Because of their importance, tremendous efforts have been made in exploring efficient methods to produce single-isomer compounds .…”