Teresa Gianferrara

A categorization of metal anticancer compounds based on their mode of action

The development of new metal anticancer compounds is a challenge for inorganic chemists. We have to face the fact that four decades of research in this field have only produced a small number of clinically used compounds, most often developed through serendipity rather than through rational chemical design. Nevertheless, by virtue of the wealth of knowledge acquired in these years, medicinal inorganic chemistry is probably mature for making significant steps forward and there are great expectations for future developments. With the aim of contributing to the rationalization of this field, we suggest here a categorization of metal anticancer compounds into five classes based on their mode of action: (i) the metal has a functional role, i.e. it must bind to the biological target; (ii) the metal has a structural role, i.e. it is instrumental in determining the shape of the compound and binding to the biological target occurs through non-covalent interactions; (iii) the metal is a carrier for active ligands that are delivered in vivo; (iv) the metal compound is a catalyst; and (v) the metal compound is photoactive and behaves as a photo-sensitizer. Selected examples for each category are given. The few metal anticancer drugs that are in clinical use are all believed to be functional compounds. Our classification, that is clearly focused on the metal compound and is independent from the nature of its bio-target(s)-most often still unknown-has the purpose of providing an intellectual tool that might be helpful in the rational development of new drugs.

Coordination and release of NO by ruthenium–dimethylsulfoxide complexes—implications for antimetastases activity

Abstract Several Ru(II) and Ru(III)–dimethylsulfoxide (DMSO) complexes, that are not cytotoxic in vitro, are endowed with anticancer and, in particular, antimetastatic activity against animal tumor models. One possibility for explaining the activity of such compounds against disseminated tumors is that they interfere with NO metabolism in vivo. Thus, we investigated the reactivity of ruthenium–chloride–DMSO complexes towards NO with the aim of producing well-characterized models to be used as reference compounds in subsequent biomimetic studies. In this contribution, we report on the synthesis, spectroscopic, structural and electrochemical characterization of anionic (e.g. [(DMSO)2H][trans-RuCl4(DMSO-O)(NO)] (1)), neutral (e.g. mer,cis-RuCl3(DMSO-O)2(NO) (2)) and new cationic (e.g. [cis,fac-RuCl2(DMSO-O)3(NO)][BF4] (9)) Ru–DMSO nitrosyls, derived from both Ru(II) and Ru(III)–chloride–DMSO precursors. Coordination of the strong π-acceptor NO favors coordination of DMSO ligands through oxygen (DMSO-O) to avoid competition for π electrons. The reactivity of some Ru–DMSO–NO complexes towards heterocyclic N-ligands, leading to compounds such as [(Im)2H][trans-RuCl4(Im)(NO)] (Im=imidazole, 6) and [cis,mer-RuCl2(py)3(NO)][BF4] (py=pyridine, 10), is also described. The spectroscopic and X-ray structural features for all these complexes are consistent with the {Ru(NO)}6 formulation, that is a diamagnetic Ru(II) nucleus bound to NO+. Electrochemical measurements on the Ru–NO complexes showed that they are all redox active in DMF solutions and the site of reduction is the NO+ moiety. With the exception of 10, the reduced complexes are not stable and rapidly release the NO radical.

New half sandwich Ru(II) coordination compounds for anticancer activity.

With the aim of expanding the structure-activity relationship investigation, the series of Ru(II) half sandwich coordination compounds of the type [Ru([9]aneS3)(chel)(L)](n+) previously described by us (where [9]aneS3 is the neutral face-capping ligand 1,4,7-trithiacyclononane, chel is a neutral or anonic chelating ligand, L = Cl(-) or dmso-S, n = 0-2) was extended to 1,4,7-triazacyclononane ([9]aneN3). In addition, new neutral N-N, and anionic N-O and O-O chelating ligands, i.e. dach (trans-1,2-diaminocyclohexane), pic(-) (picolinate), and acac(-) (acetylacetonate), were investigated in combination with both [9]aneS3 and [9]aneN3. Overall, ten new half-sandwich complexes were prepared and fully characterized and their chemical behaviour in aqueous solution was established. The single-crystal X-ray structures of eight of them, including the versatile precursor [Ru([9]aneN3)(dmso-S)(2)Cl]Cl (9), were also determined. The results of in vitro antiproliferative tests performed on selected compounds against MDA-MB-231 human mammary carcinoma cells confirmed that, in this series, only compounds that hydrolyse the monodentate ligand at a reasonable rate show moderate activity, provided that the chelate ligand is a hydrogen bond donor.

Novel water-soluble 99mTc(I)/Re(I)-porphyrin conjugates as potential multimodal agents for molecular imaging

The synthesis and characterization of two novel water soluble porphyrins with three meso pyridyl rings and one peripheral chelator - either a diethylenetriamine unit (4) or a bipyridyl fragment (8) - for binding to the {(99m)Tc(CO)3}(+) moiety is reported. In 8, despite the presence of a flexible and hydrophilic PEG-like linker that connects the bpy unit to the macrocycle, good water solubility was only obtained by methylation of the pyridyl N atoms that provided three extra positive charges. Furthermore, the water-soluble conjugates of 4 and 8 with either one fac-{Re(CO)3}(+) (9 and 10, respectively) or one fac-{(99m)Tc(CO)3}(+) fragment (9a and 10a, respectively) are described.

New half sandwich-type Ru(II) coordination compounds characterized by the fac-Ru(dmso-S)3 fragment: influence of the face-capping group on the chemical behavior and in vitro anticancer activity

The Ru(II) complex fac-[RuCl(dmso-S)(3)(dmso-O)(2)][PF(6)] (P2) was found to be an excellent precursor for the facile preparation in high yield of half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N)(2)][PF(6)] (e.g. (N)(2) = 1,2-diaminoethane (en, 4), trans-1,2-diaminocyclohexane (dach, 5), or 2 NH(3) (6)). Neutral half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N-O)] where N-O is an anionic chelating ligand (e.g. N-O = picolinate (pic, 7)) are best prepared from the universal Ru(II)-dmso precursor cis-[RuCl(2)(dmso)(4)] (P1). These complexes, that were fully characterized in solution and in the solid state, are structurally similar to the anticancer organometallic compounds [Ru(η(6)-arene)(chel)Cl][PF(6)](n) but, in place of a face-capping arene, have the fac-Ru(dmso-S)(3) fragment. In contrast to what observed for the corresponding arene compounds, that rapidly hydrolyze the Cl ligand upon dissolution in water, compounds 4-6 are very stable and inert in aqueous solution. Probably their inertness is the reason why they showed no significant cytotoxicity against the MDA-MB-231 cancer cell line.

Towards Matched Pairs of Porphyrin-ReI/99mTcIConjugates that Combine Photodynamic Activity with Fluorescence and Radio Imaging

We recently prepared two novel water soluble porphyrins bearing a single peripheral chelator, either diethylenetriamine (1) or bipyridyl (2), tethered to one meso position. The preparation of their conjugates with a fac‐{99mTc(CO)3}+ fragment and the potential of these resulting conjugates as fluorescence and radio imaging tools were also described. In this work, we focused on the corresponding non‐radioactive analogues that bear the fac‐{Re(CO)3}+ fragment (diethylenetriamine 3 and bipyridyl 4). We report on the uptake, in vitro PDT activity, and cellular localization of ReI conjugates 3 and 4 in comparison to the parent porphyrins 1 and 2. Compounds 1–4 have modest or negligible cytotoxicity in the dark against HeLa human cervical cancer cells but become remarkably cytotoxic after exposure to moderate doses of red visible light (590–700 nm). This phototoxicity was found to be directly proportional to the total light dose. Although the four compounds show distinct uptake patterns, they have comparable PDT activity. Confocal fluorescence measurements showed that porphyrin 1 and its ReI conjugate 3 have different cellular localization patterns in HeLa cells.

Pyridylporphyrins peripherally coordinated to ruthenium-nitrosyls, including the water-soluble Na4[Zn·4′TPyP{RuCl4(NO)}4]: synthesis and structural characterization

Several new ruthenium-nitrosyl conjugates with meso-4′pyridylporphyrins, namely the two anionic isomers [nBu4N][trans-RuCl4(4′MPyP)(NO)] (1) and [nBu4N][cis-RuCl4(4′MPyP)(NO)] (2), the two neutral isomers [mer,trans-RuCl3(4′MPyP)2(NO)] (3) and [mer,cis-RuCl3(4′MPyP)2(NO)] (4), and the tetraruthenated adduct [nBu4N]4[4′TPyP{RuCl4(NO)}4] (5) were obtained by reaction of [nBu4N][trans-RuCl4(dmso-O)(NO)] with 4′MPyP and 4′TPyP (meso-4′monopyridylporphyrin and meso-4′tetrapyridylporphyrin, respectively). The X-ray structures of 2, 4, and 5 are described. Exchange of nBu4N+ for Na+ eventually led to the water-soluble tetraruthenated porphyrin Na4[Zn·4′TPyP{RuCl4(NO)}4] (6·Zn).

Improved lipase-mediated resolution of mandelic acid esters by multivariate investigation of experimental factors

Abstract Lipase catalyzed stereoselective acylation of butyl mandelate was studied. The determining role of solvent and acylating agent was pointed out and a considerable inhibitory effect due to mandelic acid was observed by screening different lipases. Finally, the performance of the reaction was appreciably improved thank to a multivariate approach.

Phototoxic Activity and DNA Interactions of Water-Soluble Porphyrins and Their Rhenium(I) Conjugates.

In the search for alternative photosensitizers for use in photodynamic therapy (PDT), herein we describe two new water‐soluble porphyrins, a neutral fourfold‐symmetric compound and a +3‐charged tris‐methylpyridinium derivative, in which either four or one [1,4,7]‐triazacyclononane (TACN) units are connected to the porphyrin macrocycle through a hydrophilic linker; we also report their corresponding tetracationic ReI conjugates. The in vitro (photo)toxic effects of the compounds toward the human cell lines HeLa (cervical cancer), H460M2 (non‐small‐cell lung carcinoma), and HBL‐100 (non‐tumorigenic epithelial cells) are reported. Three of the compounds are not cytotoxic in the dark up to 100 μm, and the fourfold‐symmetric couple revealed very good phototoxic indexes (PIs). The intracellular localization of all derivatives was studied in HeLa cells by confocal fluorescence microscopy. Although low nuclear localization was observed for some of them, it still prompted us to investigate their capacity to bind both quadruplex and duplex DNA; we observed significant selectivity in the tris‐methylpyridinium derivatives for G‐quadruplex interactions.

Novel Unsymmetrical Ru(III) and Mixed-valence Ru(III)/Ru(II) Dinuclear Compounds Related to the Antimetastatic Ru(III) Drug NAMI-A.

In this paper we report the stepwise preparation and the characterization of new unsymmetrical monoanionic Ru(III) dinuclear compounds, [NH4][{trans-RuCl4(Me2SO-S)}(μ-L){mer-RuCl3(Me2SO-S)(Me2SO-O)}] (L = pyz (1), pym (2)). By a similar synthetic approach we also prepared new mixed-valence Ru(III)/Ru(II) dinuclear compounds of formula [NH4][{trans-RuCl4(Me2SO-S)}(μ-pyz){cis,cis,cis-RuCl2(Me2SO-S)2(CO)}] (L = pyrazine (pyz, 3), pyrimidine (pym, 4)). Moreover, we describe the chemical behavior of compounds 1-4 in physiological solution, also after complete reduction (with ascorbic acid) to the corresponding Ru(II)/Ru(II) species. Overall, the chemical behavior of 1 and 2 after reduction resembles that of the corresponding dianionic and neutral dinuclear species, [{trans-RuCl3(Me2SO-S)}2(μ-L)]2−and [{mer-RuCl3(Me2SO-S)(Me2SO-O)}2 (μ-L)]. On the other hand, the mixed-valence dinuclear compounds 3 and 4, owing to the great inertness of the cis,cis,cis-RuCl2(Me2SO-S)2(CO)(1/2μ-L) fragment, behave substantially like the mononuclear species [trans-RuCl4(Me2SO-S)(L)]− in which the terminally bonded L ligand can be considered as bearing a bulky substituent on the other N atom.