Synthetic strategies towards ruthenium–porphyrin conjugates for anticancer activity

Abstract

The conjugation of porphyrins to metal fragments is a strategy for making new compounds that are expected to combine the phototoxicity and the tumour-localization properties of the porphyrin chromophore with the cytotoxicity of the metal fragment for additive antitumour effect. We report here the preparation of new classes of porphyrin–ruthenium conjugates with potential bio-medical applications. Ruthenium was chosen because several Ru compounds have shown promising anticancer activity. The conjugation with the porphyrin moiety was accomplished either through peripheral pyridyl rings (e.g.meso-4′-tetrapyridylporphyrin, 4′TPyP) or through bpy units (e.g.meso-(p-bpy-phenyl)porphyrins, bpy_n-PPs, n = 1–4). The number of Ru fragments attached to the porphyrins ranges from 1 to 4 and the total charge of the conjugates from −4 to +8. Different types of peripheral fragments, both Ru(III) and Ru(II), have been used: in some cases they are structurally similar to established anticancer compounds. Examples are [Na]₄[4′TPyP{trans-RuCl₄(dmso-S)}₄] (2), that bears four NAMI-type Ru(III) fragments, or [4′TPyP{Ru([9]aneS3)(en)}₄][CF₃SO₃]₈ (3) and [bpy₄-PP{Ru([9]aneS3)(dmso-S)}₄][CF₃SO₃]₈ (9) (en = ethane-1,2-diamine, [9]aneS3 = 1,4,7-trithiacyclononane) that have four half-sandwich Ru(II) compounds. The Ru fragments may either contain one or more labile ligands, such as in 2 or in 9, or be coordinatively saturated and substitutionally inert, such as in 3 or in [bpy₄-PP{Ru([12]aneS4)}₄][CF₃SO₃]₈ (11) ([12]aneS4 = 1,4,7,10-tetrathiacyclododecane). Most of the ruthenium-porphyrin conjugates described in this work are soluble—at least moderately—in aqueous solution and are thus suitable for biological investigations, in particular for cytotoxicity and photo-cytotoxicity tests.