The novel L- and D-amino acid derivatives of hydroxyurea and hydantoins: synthesis, X-ray crystal structure study, and cytostatic and antiviral activity evaluations.

Abstract

The novel L- and D-amino acid derivatives of hydroxyurea 5a-o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a-o with hydroxylamine. The hydantoin derivatives 6a-e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among L-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC(50) = 10-19 microM) 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 (IC(50) = 4.8-83.9 microM), but not the growth of normal fibroblasts (WI 38; IC(50) > 100 microM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC(50) = 3.2 microg/mL; 6m, EC(50) = 4.0 microg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC(50) = 43.4 microg/mL; 6m, CC(50) = 12.5 microg/mL(-1)).

• Authors: Ninoslav Opacić, Monika Barbarić, Branka Zorc, Mario Cetina, Ante Nagl, Danijel Frković, Marijeta Kralj, Kresimir Pavelić, Jan Balzarini, Graciela Andrei, Robert Snoeck, Erik De Clercq, Silvana Raić-Malić, Mladen Mintas
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 2 Pg. 475-82 (Jan 27 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15658861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Antineoplastic Agents
• Antiviral Agents
• Hydantoins
• Hydroxyurea

Topics

• Amino Acids (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Cell Line, Tumor
• Crystallography, X-Ray
• Cytomegalovirus (drug effects)
• Drug Screening Assays, Antitumor
• Herpesvirus 3, Human (drug effects)
• Humans
• Hydantoins (chemical synthesis, chemistry, pharmacology)
• Hydroxyurea (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship