Synthesis and biological activity of N(alpha)-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenylacetyl]-L-glutamic acid.

Kusakiewicz-Dawid, Anna; Bugaj, Marta; Dzik, Jolanta M.; Gołos, Barbara; Wińska, Patrycja; Pawelczak, Krzysztof; Rzeszotarska, Barbara; Rode, Wojciech

doi:10.18388/abp.2002_3836

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“…pddPteSO 2 Glu and CH 3 pddPteSO 2 Glu). It should be noted that the L5178Y cells used in our experiments were 2-20-fold less sensitive to growth inhibition than L1210 cells by several known antifolates (Kusakiewicz-Dawid et al, 2002). Replacement of CONH by SO 2 NH in CH 3 pddPteGlu weakened inhibition of both the enzyme and cell growth (Tables 4-5).…”

Section: Biological Evaluationmentioning

confidence: 79%

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

Pawelczak¹,

Makowski²,

Kempny³

et al. 2002

Acta Biochim Pol

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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,

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Section: Biological Evaluationmentioning

confidence: 79%