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

• Autorzy: Pawelczak K. , Makowski M. , Kempny M. , Dzik J.M. , Golos B. , Rode W. , Rzeszotarska B.
• Języki publikacji: EN

Abstrakty

EN

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.

Słowa kluczowe

EN

dimethylformamide; enzyme inhibition; p-aminobenzenesulphonic acid; dimethylacetamide; thymidylate synthase; thymidylate synthase inhibitor; cytotoxicity; sulphamide; antifolate

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2002
• Tom: 49
• Numer: 2
• Opis fizyczny: p.407-420,fig.

Twórcy

autor

Pawelczak K.

• University of Opole, 48 Oleska St. 45-052 Opole, Poland

autor

Makowski M.

autor

Kempny M.

autor

Dzik J.M.

autor

Golos B.

autor

Rode W.

autor

Rzeszotarska B.

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