title: 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.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacića. 1, HR-10 000 Zagreb, Croatia.
authors.forename: Ninoslav
authors.initials: N
authors.lastname: Opacić
authors.forename: Monika
authors.initials: M
authors.lastname: Barbarić
authors.forename: Branka
authors.initials: B
authors.lastname: Zorc
authors.forename: Mario
authors.initials: M
authors.lastname: Cetina
authors.forename: Ante
authors.initials: A
authors.lastname: Nagl
authors.forename: Danijel
authors.initials: D
authors.lastname: Frković
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Kresimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
authors.forename: Mladen
authors.initials: M
authors.lastname: Mintas
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006827:Hydantoins; D006918:Hydroxyurea