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The Novel L- and D-Amino Acid Derivatives of Hydroxyurea and Hydantoins: Synthesis, X-Ray Crystal Structure Study, Cytostatic and Antiviral Evaluations

The novel L- and D-amino acid derivatives of hydroxyurea 5a-o were prepared by aminolysis N-(1-benzotriazolecarbonyl)-amino acid amides 4a-o with hydroxylamine. The hydantoin derivatives 6a-e, g, i were synthesized by base catalysed cyclization of amides 4, common precursor for 5 and 6. The aim for this synthesis was to determine the absolute configuration of 6. X-ray crystal structure analysis shows that the C5 atom in 6e posses S configuration which is consistent with the configuration of the starting reagent, L-leucine. This means that the configuration of the stereogenic centre, which was not involved in chemical tranformations was retained. Thus, the series of L- and D-amino acid derivatives of hydroxyurea (5a-k and 5l-o) should also posses the same configuration at the stereogenic centre as the starting amino acid. Among L-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC50: 10-19 uM) and showed selectivity with respect to normal human fibroblasts (WI 38). D-amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC50: 4.8-83.9 uM), but not the growth of normal fibroblasts. Besides that, compound carrying cyclohexanemethylamine residue 5m showed the most pronounced inhibitory effect from all examined compounds (human T-lymphocytes, Molt4/C8 ; IC50: 4.8 uM). Therefore, compounds 5m and 5o seems to be leading compounds and justify its structural optimisation for further studies. Results on antiviral evaluations showed that N-(1-benzotriazolylcarbonyl)-amino acid amide 4m and hydantoin 6i had rather expressed activity against Davis strain of CMV (4m, EC50: 3.2 uM and 6i, EC50: 4.0 uM).

L- and D-amino aAcid derivatives; hydoxyurea; hydantoins; cytostatic and antiviral evaluations; X-ray crystal structure study

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