TRASUTA: The Effect of the Structural Rigidity of a Mesocyclic AAZTA-like Chelating Agent on the Thermodynamic, Kinetic, and Structural Properties of Some Divalent Metal and Ga Complexes.

Mesocyclic chelating agents such as AAZTA and its derivatives have been recently reported to overcome the relatively low thermodynamic stability of metal complexes of acyclic chelating agents and the slow complexation kinetics of macrocyclic chelating agents. This work reports the preparation of a spirobicyclic hexadentate AAZTA-like chelating agent (TRASUTA) and the investigation of the thermodynamic, kinetic, and structural properties of the corresponding chelates with the PET-relevant Ga and selected metal ions. A combination of analytical techniques allowed identification of a coordination isomerization process, involving the coordinating side arms and the inversion of a nitrogen atom and leading to lower thermodynamic and kinetic inertness with respect to mononuclear mesocyclic analogues.

[Gd(HB-DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP-DO3A)] (Prohance).

[Gd(HP-DO3A)] (gadoteridol) as an active compound of ProHance is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long-term retention of gadolinium-based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP-DO3A)].

Modulating the Shape of Short Metal-Mediated Heteroleptic Tapes of Porphyrins.

In view of developing artificial light-responsive complex systems, the preparation of discrete and robust heteroleptic assemblies of different chromophores in precisely defined positions is of great value since they would allow to investigate directional processes unavailable in symmetrical architectures. Here we describe the preparation, through a modular stepwise approach, and characterization of four novel and robust metal-mediated heteroleptic 4+3 porphyrin tapes, labeled D -T -D , D -T -D , D -T -D , and D -T -D , where a central meso-tetrapyridylporphyrin (either 3'-TPyP=T or 4'-TPyP=T ) is connected to two equal cis-dipyridylporphyrins (either 3'cisDPyMP=D or 4'cisDPyMP=D ) through four {t,c,c-RuCl (CO) } fragments. Whereas D -T -D is flat, the tapes containing at least one 3'PyP, i.

Ruthenium(II) Polypyridyl Complexes Containing Simple Dioxo Ligands: a Structure-Activity Relationship Study Shows the Importance of the Charge.

Cancer is one of the main causes of death worldwide. Platinum complexes (i. e.

A Flexible Synthetic Strategy for the Preparation of Heteroleptic Metallacycles of Porphyrins.

We present a stepwise synthetic strategy for the preparation of the unprecedented heteroleptic 2+2 neutral metallacycle [{-RuCl(CO)}(4'DPyP)(3'DPyP)] (), in which two different 5,10--dipyridylporphyrins, 4'DPyP [i.e., 5,10-bis(4'-pyridyl)-15,20-diphenylporphyrin] and 3'DPyP [i.

cis-Locked Ru(II)-DMSO Precursors for the Microwave-Assisted Synthesis of Bis-Heteroleptic Polypyridyl Compounds.

We describe a synthetic strategy for the preparation of bis-heteroleptic polypyridyl Ru(II) complexes of the type [Ru(L1)(L2)] (L1 and L2 = diimine ligands) from well-defined Ru(II) precursors. For this purpose, a series of six neutral, anionic, and cationic -locked Ru(II)-DMSO complexes (-) of the general formula [Y] -[RuX(DMSO-S)(O-O)] (where O-O is a symmetrical chelating anion: oxalate (ox), malonate (mal), acetylacetonate (acac); X = DMSO-O or Cl; = -1/0/+1 depending on the nature and charge of X and O-O; when present, Y = K or PF) were efficiently prepared from the well-known -[RuCl(DMSO)] (). When treated with diimine chelating ligands (L1 = bpy, phen, dpphen), the compounds - afforded the target [Ru(L1)(O-O)] complex together with the undesired (and unexpected) [Ru(L1)] species.

Ruthenium(II) 1,4,7-trithiacyclononane complexes of curcumin and bisdemethoxycurcumin: Synthesis, characterization, and biological activity.

Two cationic ruthenium(II) 1,4,7-trithiacyclononane ([9]aneS) complexes of curcumin (curcH) and bisdemethoxycurcumin (bdcurcH), namely [Ru(curc)(dmso-S)([9]aneS)]Cl (1) and [Ru(bdcurc)(dmso-S)([9]aneS)]Cl (2) were prepared from the [RuCl(dmso-S)([9]-aneS)] precursor and structurally characterized, both in solution and in the solid state by X-ray crystallography. The corresponding PTA complexes [Ru(curc)(PTA)([9]aneS)]Cl (3) and [Ru(bdcurc)(PTA)([9]aneS)]Cl (4) have been also synthesized and characterized (PTA = 1,3,5-triaza-7-phosphaadamantane). Bioinorganic studies relying on mass spectrometry were performed on complexes 1-4 to assess their interactions with the model protein lysozyme.

Investigating the reactivity of neutral water-soluble Ru(ii)-PTA carbonyls towards the model imine ligands pyridine and 2,2'-bipyridine.

As a continuation of our strategy for preparing new Ru(ii) precursors to be exploited as building blocks in the construction of metal-mediated supramolecular assemblies with improved solubility in water, here we describe the reactivity of selected neutral Ru(ii)-PTA carbonyls (PTA = 1,3,5-triaza-7-phosphaadamantane) towards the model imine ligands pyridine (py) and 2,2'-bipyridine (bpy) and the preparation and characterization of several neutral and cationic water-soluble derivatives: ,,-[RuCl(CO)(py)(PTA)] (7), ,,-[RuCl(CO)(py)(PTA)] (9), ,-[Ru(bpy)Cl(CO)(PTA)]Cl (10), -[Ru(bpy)(CO)(PTA)](Cl) (12), ,-[Ru(bpy)(CO)Cl(PTA)]Cl (13), ,-[Ru(bpy)(CO)(PTA)](NO) (14NO). In addition, we found that light-induced isomerization in some bpy compounds could be induced. The following species, either side-products isolated in low yield or compounds obtained exclusively in solution, were also unambiguously identified: ,,-[RuCl(CO)(py)(PTA)] (8), -[RuCl(bpy)(CO)(PTA)] (11), ,-[Ru(bpy)Cl(CO)(PTA)]Cl (15) and ,-[Ru(bpy)(CO)Cl(PTA)]Cl (16).

Orthogonal Coordination Chemistry of PTA toward Ru(II) and Zn(II) (PTA = 1,3,5-Triaza-7-phosphaadamantane) for the Construction of 1D and 2D Metal-Mediated Porphyrin Networks.

This work demonstrates that PTA (1,3,5-triaza-7-phosphaadamantane) behaves as an orthogonal ligand between Ru(II) and Zn(II), since it selectively binds through the P atom to ruthenium and through one or more of the N atoms to zinc. This property of PTA was exploited for preparing the two monomeric porphyrin adducts with axially bound PTA, [Ru(TPP)(PTA-κ)] (, TPP = -tetraphenylporphyrin) and [Zn(TPP)(PTA-κ)] (). Next, we prepared a number of heterobimetallic Ru/Zn porphyrin polymeric networks-and two discrete molecular systems-mediated by -bridging PTA in which either both metals reside inside a porphyrin core, or one metal belongs to a porphyrin, either Ru(TPP) or Zn(TPP), and the other to a complex or salt of the complementary metal (i.

A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent.

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin.

NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry.

NAMI-A ((ImH)[-RuCl(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[-RuCl(Ind)], Ind = indazole; KP1339 = Na[-RuCl(Ind)]) are two structurally related ruthenium(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemistry scientific community as promising anticancer drug candidates. This has led to a considerable amount of studies on their respective chemico-biological features and to the eventual admission of both to clinical trials. The encouraging pharmacological performances qualified KP1019 mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers, whereas the non-cytotoxic NAMI-A has gained the reputation of being a very effective antimetastatic drug.

Rare Example of Stereoisomeric 2 + 2 Metallacycles of Porphyrins Featuring Chiral-at-Metal Octahedral Ruthenium Corners.

In this paper, we describe three new stereoisomers of the already known 2 + 2 metallacycle of porphyrins [ trans, cis, cis-RuCl(CO)(4' cisDPyP)] (2, 4' cisDPyP = 5,10-bis(4'-pyridyl)-15,20-diphenylporphyrin), namely [{ trans,cis,cis-RuCl(CO)}(4' cisDPyP){ cis,cis,cis-RuCl(CO)}] (14) and [ cis,cis,cis-RuCl(CO)(4' cisDPyP)] (15), in which the chiral { cis,cis,cis-RuCl(CO)} fragment has either a C or A handedness. The least abundant 15 exists as a mixture of two stereoisomers defined as alternate (15, both porphyrins are trans to a Cl and a CO) and pairwise (15, one porphyrin is trans to two chlorides and the other to two carbonyls), each one as a statistical mixture of meso ( AC) and racemic ( AA and CC) diastereomers. Remarkably, both 14 and 15 are-to the best of our knowledge-unprecedented examples of 2D metallacycles with octahedral chiral-at-metal connectors, and 14 is the first example of a 2 + 2 molecular square with stereoisomeric Ru(II) corners.

Ru(ii)-Peptide bioconjugates with the cppH linker (cppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid): synthesis, structural characterization, and different stereochemical features between organic and aqueous solvents.

Three new Ru(ii) bioconjugates with the C-terminal hexapeptide sequence of neurotensin, RRPYIL, namely trans,cis-RuCl2(CO)2(cppH-RRPYIL-κNp) (7), [Ru([9]aneS3)(cppH-RRPYIL-κNp)(PTA)](Cl)2 (8), and [Ru([9]aneS3)Cl(cppH-RRPYIL-κNp)]Cl (11), where cppH is the asymmetric linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid, were prepared in pure form and structurally characterized in solution. The cppH linker is capable of forming stereoisomers (i.e.

The NAMI A - human ferritin system: a biophysical characterization.

The reaction of the antimetastatic ruthenium(iii) drug NAMI A with human H-chain ferritin (HuHf) was investigated through a variety of biophysical methods. We observed that the addition of HuHf to NAMI A solutions significantly increases the rate of spontaneous NAMI A hydrolysis suggesting the occurrence of a direct metallodrug-protein interaction. The resulting hydrolyzed Ru species binds the protein mostly forming a relatively tight 1 : 1 ruthenium/ferritin (subunit) adduct that was then separated and characterized.

Water-Soluble Ruthenium(II) Carbonyls with 1,3,5-Triaza-7-phosphoadamantane.

As a continuation of our strategy for preparing new Ru(II) precursors with improved water solubility through the introduction of highly water-soluble 1,3,5-triaza-7-phosphoadamantane (PTA) supporting ligands in the coordination sphere, in this work, we address the largely unexplored preparation of Ru(II)-PTA carbonyls. Two complementary synthetic approaches were used: (1) the treatment of a series of neutral Ru(II)-CO-dmso compounds of general formula RuCl(CO) (dmso) ( n = 1-3, 1-5) with PTA; (2) the reaction of Ru(II)-PTA complexes with CO. Through the first approach, we obtained and fully characterized seven novel neutral compounds bearing from one to three PTA ligands per Ru atom, namely, the four monocarbonyls, cis, cis, trans-RuCl(CO)(dmso-S)(PTA) (6), trans-RuCl(CO)(PTA) (7), cis, mer-RuCl(CO)(PTA) (8), and trans, trans, trans-RuCl(CO)(OH)(PTA) (10), and the three dicarbonyls, trans, trans, trans-RuCl(CO)(PTA) (11), [RuCl(CO)(PTA)] (12), and cis, cis, trans-RuCl(CO)(PTA) (13).

The Deceptively Similar Ruthenium(III) Drug Candidates KP1019 and NAMI-A Have Different Actions. What Did We Learn in the Past 30 Years?

The general interest in anticancer metal-based drugs and some encouraging pharmacological results obtained at the beginning of the investigations on innovative Ru-based drugs triggered a lot of attention on NAMI-A and KP1019, the two Ru(III) coordination compounds that are the subject of this review. This great attention led to a considerable amount of scientific results and, more importantly, to their eventual admission into clinical trials. Both complexes share a relatively low systemic toxicity that allows reaching rather high dosages, comparable to those of carboplatin.

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 Re(I) 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).

(15)N NMR spectroscopy unambiguously establishes the coordination mode of the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) in Ru(ii) complexes.

We investigated the reactivity of three Ru(ii) precursors -trans,cis,cis-[RuCl2(CO)2(dmso-O)2], cis,fac-[RuCl2(dmso-O)(dmso-S)3], and trans-[RuCl2(dmso-S)4] - towards the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) or its parent compound 4-methyl-2-(2'-pyridyl)pyrimidine ligand (mpp), in which a methyl group replaces the carboxylic group on the pyrimidine ring. In principle, both cppH and mpp can originate linkage isomers, depending on how the pyrimidine ring binds to ruthenium through the nitrogen atom ortho (N(o)) or para (N(p)) to the group in position 4. The principal aim of this work was to establish a spectroscopic fingerprint for distinguishing the coordination mode of cppH/mpp also in the absence of an X-ray structural characterization.

Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy.

Background: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment.

Methods: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored.

NAMI-A is highly cytotoxic toward leukaemia cell lines: evidence of inhibition of KCa 3.1 channels.

We report here that the established anticancer ruthenium(iii) complex NAMI-A induces potent and selective cytotoxic effects in a few leukaemia cell lines. These results sound very surprising after 20 years of intense studies on NAMI-A, commonly considered as a "non-cytotoxic" antimetastatic agent. In addition, evidence is given for selective inhibition of KCa 3.

New water-soluble ruthenium(II) terpyridine complexes for anticancer activity: synthesis, characterization, activation kinetics, and interaction with guanine derivatives.

With the aim of assessing whether ruthenium(II) compounds with meridional geometry might be utilized as potential antitumor agents, a series of new, water-soluble, monofunctional ruthenium(II) complexes of the general formula mer-[Ru(L3)(N-N)X][Y]n (where L3 = 2,2':6',2″-terpyridine (tpy) or 4'-chloro-2,2':6',2″-terpyridine (Cl-tpy), N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach), or 2,2'-bipyridine (bpy); X = Cl or dmso-S; Y = Cl, PF6, or CF3SO3; n = 1 or 2, depending on the nature of X) were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and for three of them, i.e.

Towards matched pairs of porphyrin-Re(I) /(99m) Tc(I) conjugates 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-{(99m) Tc(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).

New cationic and neutral Ru(II)- and Os(II)-dmso carbonyl compounds.

The preparation and structural characterization of three cationic Ru(II)-dmso carbonyls and of four neutral mono- and dicarbonyl Os(II)-dmso derivatives is reported. The two monocarbonyl species fac-[Ru(CO)(dmso-O)3(dmso-S)2][PF6]2 (11) and cis,cis,cis-[RuCl(CO)(dmso-O)2(dmso-S)2][PF6] (12) were obtained from the neutral monocarbonyl precursor cis,trans,cis-[RuCl2(CO)(dmso-O)(dmso-S)2] (3) upon stepwise replacement of the chlorides with dmso, that binds in each case through the oxygen atom. The dicarbonyl cationic complex cis,cis,trans-[Ru(CO)2(dmso-O)2(dmso-S)Cl][PF6] (13) was instead obtained upon treatment of the neutral tricarbonyl precursor fac-[RuCl2(CO)3(dmso-O)] (8) with AgPF6 in the presence of DMSO: replacement of a Cl(-) with a dmso-O implied also the substitution of one CO ligand by another dmso (that binds through S trans to Cl).

New uses for old drugs: attempts to convert quinolone antibacterials into potential anticancer agents containing ruthenium.

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ(2)O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4. The complexes bind to serum proteins displaying relatively high binding constants.

Novel water-soluble (99m)Tc(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.