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

• Authors: Krzysztof Pawełczak , Maciej Makowski , Michał Kempny , Jolanta M Dzik , Barbara Gołos , Wojciech Rode , Barbara Rzeszotarska
• Languages of publication: EN

Abstracts

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.

Keywords

EN

thymidylate synthase inhibitors; antifolate analogues; antifolates; p-aminobenzenesulfonic acid

• Journal: Acta Biochimica Polonica
• Year: 2002
• Volume: 49
• Issue: 2
• Pages: 407-420

Dates

published

2002

received

2002-06-01

accepted

2002-06-05

Contributors

author

Krzysztof Pawełczak

• Institute of Chemistry, University of Opole, Opole, Poland

author

Maciej Makowski

• Institute of Chemistry, University of Opole, Opole, Poland

author

Michał Kempny

• Institute of Chemistry, University of Opole, Opole, Poland

author

Jolanta M Dzik

• Nencki Institute of Experimental Biology, Warszawa, Poland

author

Barbara Gołos

• Nencki Institute of Experimental Biology, Warszawa, Poland

author

Wojciech Rode

• Nencki Institute of Experimental Biology, Warszawa, Poland

author

Barbara Rzeszotarska

• Institute of Chemistry, University of Opole, Opole, Poland

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