RESUMEN

Four mononuclear [(L-L)2 Ru(tatpp)]2+ and two dinuclear [(L-L)2 Ru(tatpp)Ru(L-L)2 ]4+ ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4 phen) or 4,7-diphenyl-1,10-phenanthroline (Ph2 phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7. These, plus several structurally related but non-redox-active RPCs, were screened for DNA cleavage activity, cytotoxicity, acetylcholinesterase (AChE) inhibition, and acute mouse toxicity, and their activities were examined with respect to redox activity and lipophilicity. All of the redox-active RPCs show single-strand DNA cleavage in the presence of GSH, whereas none of the non-redox-active RPCs do. Low-micromolar cytotoxicity (IC50 ) against malignant H358, CCL228, and MCF7 cultured cell lines was mainly restricted to the redox-active RPCs; however, they were substantially less toxic toward nonmalignant MCF10 cells. The IC50 values for AChE inhibition in cell-free assays and the acute toxicity of RPCs in mice revealed that whereas most RPCs show potent inhibitory action against AChE (IC50 values <15 µm), Ru-tatpp complexes as a class are surprisingly well tolerated in animals relative to other RPCs.

Asunto(s)

Antineoplásicos/farmacología , Inhibidores de la Colinesterasa/farmacología , Complejos de Coordinación/farmacología , Rutenio/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/toxicidad , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , División del ADN/efectos de los fármacos , Humanos , Ligandos , Espectrometría de Masas , Dosis Máxima Tolerada , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Oxidación-Reducción , Espectroscopía de Protones por Resonancia Magnética

RESUMEN

Two new ruthenium(II) polypyridyl dimers containing the large planar aromatic bridging ligands 9,11,20,22-tetraazatetrapyrido[3,2-a:2'3'-c:3' ',2''-l:2''',3'''-n]pentacene (tatpp) and 9,11,20,22-tetraazatetrapyrido[3,2-a:2'3'-c:3'',2' '-l:2''',3'''-n]pentacene-10,21-quinone (tatpq) have been synthesized and characterized by (1)H and (13)C NMR, MALDI mass spectrometry, and elemental analyses. The electronic properties (UV-vis, redox, photophysical) of these dimers are analyzed in the context of orbital calculations (PM3 level) on the bridging ligands. A localized orbital model is proposed in which low-lying acceptor orbitals on the center portion of the ligands effectively quench the Ru(II)-based MLCT emission via a mechanism that can be viewed as intramolecular electron transfer to specific subunits of the bridges.