title: Design, synthesis and biological evaluation of (E)-2-(2-arylhydrazinyl)quinoxalines, a promising and potent new class of anticancer agents.
abstract: A series of forty-seven quinoxaline derivatives, 2-(XYZC6H2CHN-NH)-quinoxalines, 1, have been synthesized and evaluated for their activity against four cancer cell lines: potent cytotoxicities were found (IC50 ranging from 0.316 to 15.749 μM). The structure-activity relationship (SAR) analysis indicated that the number, the positions and the type of substituents attached to the aromatic ring are critical for biological activity. The activities do not depend on the electronic effects of the substituents nor on the lypophilicities of the molecules. A common feature of active compounds is an ortho-hydroxy group in the phenyl ring. A potential role of these ortho-hydroxy derivatives is as N,N,O-tridentate ligands complexing with a vital metal, such as iron, and thereby preventing proliferation of cells. The most active compound was (1: X,Y=2,3-(OH)2, Z=H), which displayed a potent cytotoxicity comparable to that of the reference drug doxorubicin.
authors.affiliation: Laboratório de Oncologia Experimental, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: Felipe A R
authors.initials: FA
authors.lastname: Rodrigues
authors.affiliation: Laboratório de Oncologia Experimental, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: Igor da S
authors.initials: Ida S
authors.lastname: Bomfim
authors.affiliation: Laboratório de Oncologia Experimental, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Cavalcanti
authors.affiliation: Laboratório de Oncologia Experimental, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
authors.forename: Claudia do Ó
authors.initials: Cdo Ó
authors.lastname: Pessoa
authors.affiliation: FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil; Department of Chemistry, University of Aberdeen, Old Aberdeen AB 24 3UE, Scotland, UK.
authors.forename: James L
authors.initials: JL
authors.lastname: Wardell
authors.affiliation: CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, Scotland, UK.
authors.forename: Solange M S V
authors.initials: SM
authors.lastname: Wardell
authors.affiliation: FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil.
authors.forename: Alessandra C
authors.initials: AC
authors.lastname: Pinheiro
authors.affiliation: Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68563, 21945-970 Rio de Janeiro, Brazil.
authors.forename: Carlos Roland
authors.initials: CR
authors.lastname: Kaiser
authors.affiliation: FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68563, 21945-970 Rio de Janeiro, Brazil.
authors.forename: Thais C M
authors.initials: TC
authors.lastname: Nogueira
authors.affiliation: Department of Chemistry, University of Aberdeen, Old Aberdeen AB 24 3UE, Scotland, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Low
authors.affiliation: REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua Campo Alegre, 687, P-4169-007, Porto P-4200-150, Portugal.
authors.forename: Ligia R
authors.initials: LR
authors.lastname: Gomes
authors.affiliation: FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil. Electronic address: marcos_souza@far.fiocruz.br.
authors.forename: Marcus V N
authors.initials: MV
authors.lastname: de Souza
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry; D008024:Ligands; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D011810:Quinoxalines; D004317:Doxorubicin; D007501:Iron
keywords: Antitumor activity; Drugs; Hydrazone; Quinoxaline