New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents
Ariane C.C. de Melo,
Jaime M.S.V.P. Santana,
Kelen J.R.C. Nunes,
Bernardo L. Rodrigues,
Nathalia Castilho,
Philipe Gabriel,
Adolfo H. Moraes,
Mayra de A. Marques,
Guilherme A.P. de Oliveira,
Ívina P. de Souza,
Hernán Terenzi,
Elene C. Pereira-Maia
Affiliations
Ariane C.C. de Melo
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Jaime M.S.V.P. Santana
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Kelen J.R.C. Nunes
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Bernardo L. Rodrigues
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Nathalia Castilho
Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040900, SC, Brazil
Philipe Gabriel
Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040900, SC, Brazil
Adolfo H. Moraes
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Mayra de A. Marques
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941590, RJ, Brazil
Guilherme A.P. de Oliveira
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941590, RJ, Brazil
Ívina P. de Souza
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Hernán Terenzi
Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040900, SC, Brazil
Elene C. Pereira-Maia
Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2′-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine—one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes’ preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115.
