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-RuCl(4)(dmso-S)}(4)] (2), that bears four NAMI-type Ru(III) fragments, or [4'TPyP{Ru([9]aneS3)(en)}(4)][CF(3)SO(3)](8) (3) and [bpy(4)-PP{Ru([9]aneS3)(dmso-S)}(4)][CF(3)SO(3)](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 [bpy(4)-PP{Ru([12]aneS4)}(4)][CF(3)SO(3)](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.

Redox activation of metal-based prodrugs as a strategy for drug delivery

“…The number of Ru fragments attached to the porphyrins ranged from 1 to 4. Conjugation of porphyrins to the Ru center was an attempt to obtain additive antitumor effects originating from the phototoxic and tumor-localizing properties of the porphyrin together with the cytotoxic properties of Ru(III) [70]. Thus far, however, the compounds have not been tested in vitro or in vivo.…”

Neutral 1,3,5‐Triaza‐7‐phosphaadamantane‐Ruthenium(II) Complexes as Precursors for the Preparation of Highly Water‐Soluble Derivatives

“…In this manuscript, we report a thorough investigation of the chemical behavior of the isomers 1 and 2 in water and other coordinating solvents as well as their reactivity towards 2,2′‐bipyridine (bpy), which was used as a model for chelating diimine linkers (i.e., cppH and bpyAc). Such linkers might allow us to connect a {RuCl x (PTA) y } fragment ( x = 0–2, y = 2–4, x + y = 4) to an appropriately functionalized porphyrin through the formation of an amidic or esteric bond , . The new derivatives mer ‐[Ru(bpy)Cl(PTA) 3 ]Cl ( 9 ) and fac ‐[Ru(bpy)Cl(PTA) 3 ]Cl ( 10 ) were prepared and characterized.…”

Neutral and cationic ruthenium carbonyl complexes [Ru(CO)(2,2′-dipyridylamine)(PR3)Cl2] and [Ru(CO)(N–N)(PPh3)2(H)]Cl: synthesis, structural characterization and transfer-hydrogenation

“…In this work, the catalytic activity for the reduction of acetophenone of complexes [Ru(CO)(dpa)(PR 3 Complexes 1-5 were applied as pre-catalysts for the reduction of acetophenone as a model substrate under hydrogen-transfer conditions, using isopropanol as both solvent and hydrogen source, and KOH as co-catalyst at 82°C (see Scheme 1). The reactions were conducted at two catalyst/base/substrate molar ratios, namely 1/20/500 and 1/20/1,000, and the results are summarized in Table 4.…”

“…Crystallographic data for complexes trans-[Ru(CO)(dap) (PPh 3 General conditions: Isopropanol as hydrogen source, complexes (10 lmol/2.5 mmol L -1 ), KOH (0.2 mmol/0.05 mol L -1 ), T = 82°C a Acetophenone (10 mmol/2.5 mol L -1 ) b Acetophenone (5 mmol-1.25 mol L -1 ) …”

“…The coordination chemistry of ruthenium finds a wide range of applications, for example, in catalysis and chemotherapy [1][2][3]. Ruthenium complexes with phosphine ligands are particularly interesting due to their potential application as catalysts in several organic transformations [4][5][6][7][8], due to the possibility of modulating the properties of the complexes by changing the steric and electronic characteristics of the phosphines [9,10].…”