Complex formation of ML324, the histone demethylase inhibitor, with essential metal ions: Relationship between solution chemistry and anticancer activity.

N-(3-(dimethylamino)propyl-4-(8-hydroxyquinolin-6-yl)benzamide (ML324, HL) is a potent inhibitor of the iron-containing histone demethylase KDM4, a recognized potential target of cancer therapeutics. Herein, we report the proton dissociation and complex formation processes of ML324 with essential metal ions such as Fe(II), Fe(III), Cu(II) and Zn(II) using UV-visible, fluorescence, electron paramagnetic resonance and H NMR spectroscopic methods. The electrochemical behaviour of the copper and iron complexes was characterized by cyclic voltammetry and spectroelectrochemistry.

A complete nicotinate degradation pathway in the microbial eukaryote Aspergillus nidulans.

Several strikingly different aerobic and anaerobic pathways of nicotinate breakdown are extant in bacteria. Here, through reverse genetics and analytical techniques we elucidated in Aspergillus nidulans, a complete eukaryotic nicotinate utilization pathway. The pathway extant in this fungus and other ascomycetes, is quite different from bacterial ones.

Characterization of copper(II) specific pyridine containing ligands: Potential metallophores for Alzheimer's disease therapy.

Two amide group containing pyridine derivatives, N-(pyridin-2-ylmethyl)picolinamide (PMPA) and N-(pyridin-2-ylmethyl)-2-((pyridin-2-ylmethyl)amino)acetamide (DPMGA), have been investigated as potential metallo-phores in the therapy of Alzheimer's disease. Their complex formation with Cu(II) and Zn(II) were characterized in details. Unexpectedly not only the Cu(II) but also the Zn(II) was able to induce deprotonation of the amide-NH, however, it occurred only at higher pH or at higher metal ion concentrations than the biological conditions.

Speciation of Metal Complexes of Medicinal Interest: Relationship between Solution Equilibria and Pharmaceutical Properties.

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids.

Vanadium(IV/V) complexes of Triapine and related thiosemicarbazones: Synthesis, solution equilibrium and bioactivity.

The stoichiometry and thermodynamic stability of vanadium(IV/V) complexes of Triapine and two related α(N)-heterocyclic thiosemicarbazones (TSCs) with potential antitumor activity have been determined by pH-potentiometry, EPR and (51)V NMR spectroscopy in 30% (w/w) dimethyl sulfoxide/water solvent mixtures. In all cases, mono-ligand complexes in different protonation states were identified. Dimethylation of the terminal amino group resulted in the formation of vanadium(IV/V) complexes with considerably higher stability.

Solution equilibria of anticancer ruthenium(II)-(η(6)-p-cymene)-hydroxy(thio)pyr(id)one complexes: impact of sulfur vs. oxygen donor systems on the speciation and bioactivity.

Stoichiometry and stability of antitumor ruthenium(II)-η(6)-p-cymene complexes of bidentate (O,O) hydroxypyrone and (O,S) hydroxythiopyr(id)one type ligands were determined by pH-potentiometry, (1)H NMR spectroscopy and UV-Vis spectrophotometry in aqueous solution and in dependence of chloride ion concentration. Formation of mono-ligand complexes with moderate stability was found in the case of the hydroxypyrone ligands (ethyl maltol and allomaltol) predominating at the physiological pH range. These complexes decompose to the dinuclear tri-hydroxido bridged species [{Ru(II)(η(6)-p-cymene)}2(OH)3](+) and to the metal-free ligand at basic pH values.

A novel V(IV)O-pyrimidinone complex: synthesis, solution speciation and human serum protein binding.

The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3-dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5-hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid-base properties of 1 are studied by potentiometric and spectrophotometric methods, the pK(a) values being 1.14 and 6.

Interaction of vanadium(IV) with human serum apo-transferrin.

The interaction of V(IV)O-salts as well as of a few V(IV)O(carrier)n complexes with human serum transferrin (hTF) is studied focusing on the determination of the nature and stoichiometry of the binding of V(IV)O(2+) to hTF, as well as whether the conformation of hTF upon binding to V(IV)O(2+) or to its complexes is changed. Circular dichroism (CD) spectra measured for solutions containing V(IV)O(2+) and apo-hTF, and V(IV)O-maltol and apo-hTF, clearly indicate that hTF-V(IV)O-maltol ternary species form with a V(IV)O:maltol stoichiometry of 1:1. For V(IV)O salts and several V(IV)O(carrier)n complexes (carrier ligand=maltolato, dhp, picolinato and dipicolinato) (Hdhp=1,2-dimethyl-3-hydroxy-4-pyridinone) the maximum number of V(IV)O(2+) bound per mole of hTF is determined to be ~2 or lower in all cases.

Molybdenum(VI) coordination chemistry of the N,N-disubstituted bis(hydroxylamido)-1,3,5-triazine ligand, H2bihyat. Water-assisted activation of the Mo(VI)═O bond and reversible dimerization of cis-[Mo(VI)O2(bihyat)] to [Mo(VI)2O4(bihyat)2(H2O)2].

Reaction of the N,N-disubstituted bis(hydroxylamino) ligand 2,6-bis[hydroxy(methyl)amino]-4-morpholino-1,3,5-triazine (H(2)bihyat) with cis-[Mo(VI)O(2)(acac)(2)] in tetrahydrofuran resulted in isolation of the mononuclear compound cis-[Mo(VI)O(2)(bihyat)] (1). The treatment of Na(2)Mo(VI)O(4)·2H(2)O with the ligand H(2)bihyat in aqueous solution gave the dinuclear compounds cis-[Mo(VI)(2)O(4)(bihyat)(2)(H(2)O)(2)] (2) and trans-[Mo(VI)(2)O(4)(bihyat)(2)(H(2)O)(2)] (3) at pH values of 3.5 and 5.

Clarifying the mechanism of cation exchange in Ca(II)[15-MC(Cu(II)ligand)-5] complexes.

The calcium metallacrown Ca(II)[15-MC(Cu(II)N(Trpha))-5](2+) was obtained by self-assembly of Ca(II), Cu(II), and tryptophanhydroxamic acid. Its X-ray structure shows that the core calcium ion is well-encapsulated in the five oxygen cavity of the metallacrown scaffold. The kinetics of Ca-Ln core metal substitution was studied by visible spectrophotometry by addition of Ln(III) nitrate to solutions of Ca(II)[15-MC(Cu(II)N(Trpha))-5](2+) in methanol solution at pH 6.

[RuII(η⁵-C₅H₅)(bipy)(PPh₃)]⁺, a promising large spectrum antitumor agent: cytotoxic activity and interaction with human serum albumin.

Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy. We present results on the in vitro antitumor activity of an organometallic 'Ru(II)Cp' complex, [Ru(II)Cp(bipy)(PPh(3))][CF(3)SO(3)], designated as TM34 (PPh(3) = triphenylphosphine; bipy = 2,2'-bipyridine), against a panel of human tumor cell lines with different responses to cisplatin treatment, namely ovarian (A2780/A2780cisR, cisplatin sensitive and resistant, respectively), breast (MCF7) and prostate (PC3) adenocarcinomas. TM34 is very active against all tumorigenic cell lines, its efficacy largely surpassing that of cisplatin (CisPt).

Evaluation of the binding of oxovanadium(IV) to human serum albumin.

The understanding of the biotransformations of insulin mimetic vanadium complexes in human blood and its transport to target cells is an essential issue in the development of more effective drugs. We present the study of the interaction of oxovanadium(iv) with human serum albumin (HSA) by electron paramagnetic resonance (EPR), circular dichroism (CD) and visible absorption spectroscopy. Metal competition studies were done using Cu(II) and Zn(II) as metal probes.

Metallo-allixinate complexes with anti-diabetic and anti-metabolic syndrome activities.

Metabolic syndrome and the accompanied diabetes mellitus are both important diseases worldwide due to changes of lifestyle and eating habits. The number of patients with diabetes worldwide is estimated to increase to 300 million by 2025 from 150-220 million in 2010. There are two main types of diabetes.

Tris-(hydroxyamino)triazines: high-affinity chelating tridentate O,N,O-hydroxylamine ligand for the cis-V(V)O2(+) cation.

The treatment of the trichloro-1,3,5-triazine with N-methylhydroxylamine hydrochloride results in the replacement of the three chlorine atoms of the triazine ring with the function -N(OH)CH(3) yielding the symmetrical tris-(hydroxyamino)triazine ligand H(3)trihyat. Reaction of the ligand H(3)trihyat with NaV(V)O(3) in aqueous solution followed by addition of Ph(4)PCl gave the mononuclear vanadium(V) compound Ph(4)P[V(V)O(2)(Htrihyat)] (1). The structure of compound 1 was determined by X-ray crystallography and indicates that this compound has a distorted square-pyramidal arrangement around vanadium.

Multinuclear NMR and molecular modelling investigations on the structure and equilibria of complexes that form in aqueous solutions of Ca(2+) and gluconate.

Complexation of d-gluconate (Gluc(-)) with Ca(2+) has been investigated via (1)H, (13)C and (43)Ca NMR spectroscopy in aqueous solutions in the presence of high concentration background electrolytes (1MI4M (NaCl) ionic strength). From the ionic strength dependence of its formation constant, the stability constant at 6pH11 and at I-->0M has been derived (logK(1,1)(0)=1.8+/-0.

Vanadate complexes in serum: a speciation modeling study.

The speciations of two drug candidate ligands, 2-hydroxypyridine-N-oxide (Hhpno) and 2-mercaptopyridine-N-oxide (Hmpno), with vanadate (V(V)) were determined at 25.0 degrees C and 0.20 mol dm(-3) KCl by pH-metric and (51)V-NMR methods.

Biospeciation of various antidiabetic V(IV)O compounds in serum.

The interactions of various insulin mimetic oxovanadium(IV) compounds with serum proteins were studied in model systems and in ex vivo samples. For the modeling study, an earlier in situ method was extended and applied to the formation of ternary complexes of apotransferrin (apoTf)-V(IV)O-maltol (mal) and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhp). Both systems were evaluated via simultaneous CD and EPR measurements.

The correlation of 113Cd NMR and 111mCd PAC spectroscopies provides a powerful approach for the characterization of the structure of Cd(II)-substituted Zn(II) proteins.

Cd(II) has been used as a probe of zinc metalloenzymes and proteins because of the spectroscopic silence of Zn(II). One of the most commonly used spectroscopic techniques is (113)Cd NMR; however, in recent years (111m)Cd Perturbed Angular Correlation spectroscopy ((111m)Cd PAC) has also been shown to provide useful structural, speciation and dynamics information on Cd(II) complexes and biomolecules. In this article, we show how the joint use of (113)Cd NMR and (111m)Cd PAC spectroscopies can provide detailed information about the Cd(II) environment in thiolate-rich proteins.

Comparative studies on the biospeciation of antidiabetic VO(IV) and Zn(II) complexes.

The speciation of several insulin-mimetic/enhancing VO(IV) and Zn(II) complexes in human blood serum was studied and a comparison was made concerning the ability of the serum components to interact with the original metal complexes and the distribution of the metal ions between the low and the high molecular fractions of the serum. It was found that the low molecular mass components may play a larger role in transporting Zn(II) than in the case with VO(IV). Among the high molecular mass serum proteins, transferrin is the primary binder of VO(IV), and albumin is that of Zn(II).

Vanadium(V) compounds with the bis-(hydroxylamino)-1,3,5-triazine ligand, H2bihyat: synthetic, structural, and physical studies of [V2(V)O3(bihyat)2] and of the enhanced hydrolytic stability species cis-[V(V)O2(bihyat)]-.

Reaction of the ligand 2,6-bis[hydroxy(methyl)amino]-4-morpholino-1,3,5-triazine (H(2)bihyat) with NaV(V)O(3) in aqueous solution followed by addition of either Ph(4)PCl or C(NH(2))(3)Cl, respectively, gave the mononuclear vanadium(V) compounds Ph(4)P[V(V)O(2)(bihyat)].1.5H(2)O (1) and C(NH(2))(3)[V(V)O(2)(bihyat)] (2).

Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes.

Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx)(2)) with allixin, which is isolated from dry garlic, with a Zn(O(4)) coordination environment, exhibited high anti-diabetic effects in obesity-linked type 2 diabetic KKA(y) mice. However, this complex exhibited low activity when administered orally. To improve the effect of Zn(alx)(2), we prepared a novel Zn(II) complex with the allixin-derivative bis(1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4- thionato)Zn(II), abbreviated as Zn(II)-thioallixin-N-methyl (Zn(tanm)(2)), having a Zn(S(2)O(2)) coordination environment; this complex has extremely high in vitro insulin-like activity.

Oxovanadium(IV) complexes of salicyl-L-aspartic acid and salicylglycyl-L-aspartic acid.

The dipeptide and tripeptide analogues salicyl-L-aspartic acid (Sal-L-Asp) and salicylglycyl-L-aspartic acid (SalGly-L-Asp) were synthesized and their protonation and complex formation with V(IV)O2+ were studied in aqueous solution through the use of pH-potentiometry and spectroscopic (UV-Vis, CD and EPR) techniques. The phenolate terminus proved to be a good anchoring site to promote (i) the metal ion-induced deprotonation and subsequent coordination of the peptide amide group(s) in the pH range 4-5 for the dipeptide analogue, (ii) and in the pH range 5-6 in a very cooperative way for the tripeptide analogue. The results suggest that the presence of good anchoring donors on both sides of the amide groups is responsible for the cooperative deprotonation of the two amide-NH groups.

Vanadium(IV,V) complexes of D-saccharic and mucic acids in aqueous solution.

The vanadium(IV,V) complexes formed with two aldaric acids (D-saccharic or D-glucaric acid, and mucic or galactaric acid) in aqueous solution were characterised by employing pH-potentiometry, EPR, multinuclear NMR and UV-VIS spectroscopy. The stoichiometry and stability constants of the complexes formed were determined at 25 degrees C and ionic strength I= 0.2 mol dm(-3)(KCl).

N,N'-ethylenebis(pyridoxylideneiminato) and N,N'-ethylenebis(pyridoxylaminato): synthesis, characterization, potentiometric, spectroscopic, and DFT studies of their vanadium(IV) and vanadium(V) complexes.

The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H(2)pyr(2)en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H(2)pyr(2)en with NaBH(4) yielded the reduced Schiff base N,N'-ethylenebis(pyridoxylaminato) (H(2)Rpyr(2)en, 2); their crystal structures were determined by X-ray diffraction. The totally protonated forms of 1 and 2 correspond to H(6)L(4+), and all protonation constants were determined by pH-potentiometric and (1)H NMR titrations. Several vanadium(IV) and vanadium(V) complexes of these and other related ligands were prepared and characterized in solution and in the solid state.

Chemical speciation of insulinomimetic VO(IV) complexes of pyridine-N-oxide derivatives: binary and ternary systems.

In order to estimate the impact of the low-molecular-mass (l.m.m.