Abstract
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.
Highlights
The discovery of the cytotoxic effects of cis-diamminedichloroplatinum(II), or cisplatin, in the 1960s, by Rosenberg et al prompted the search for other antitumoral metal compounds that could be used to treat cancer [1]
The described pharmacological properties of sulfonamides and those of ruthenium complexes stimulated us to study the antitumoral potential of ternary complexes of ruthenium(II) containing a sulfonamide and a N-donor heterocyclic as ligands
This work reports on the synthesis and characterization of two complexes of ruthenium(II) with sulfamethoxypyridazine and either 1,10-phenanthroline or 2,20 -bipyridine as ligands (Figure 1)
Summary
The discovery of the cytotoxic effects of cis-diamminedichloroplatinum(II), or cisplatin, in the 1960s, by Rosenberg et al prompted the search for other antitumoral metal compounds that could be used to treat cancer [1]. (1H-imidazole)ruthenate(III) or NAMI-A, its sodium analogue or IT-139, and the indazolium trans-tetrachlorobis(1H-indazole)ruthenate(III) or KP1019, entered clinical trials. In spite of their structural and chemical similarities, KP1019 and NAMI-A show distinct antitumor patterns: NAMI-A is more effective against cancer metastases than against primary tumors, whereas the activity of KP1019 is predominantly due more to direct cytotoxic effects than to an interference with the process of tumor cell invasion and metastasis [10,11,12,13,14]
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