Julio Benítez

Vanadium polypyridyl compounds as potential antiparasitic and antitumoral agents: New achievements

In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [V(IV)O(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC(50) values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC(50) 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC(50) 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC(50) 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC(50) values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells.

Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity.

Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [V(IV)O(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1-L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial-equatorial mode. The EPR and (51)V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of V(IV) to V(V) takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [V(IV)O(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [V(IV)O(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1-L7 tmp complexes were screened by computational modeling, comparing their DNA-binding features with those of previously reported [V(IV)O(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action.

New Re(III) complexes with alkylthioureas as precursors to other Re(III) compounds. Crystal structures of [Re(N-ethylthiourea)6](PF6)3 and [Re(N,N′-dimethylthiourea)6](PF6)3

Abstract New Re(III) complexes with thiourea derivatives have been synthesized by reduction of perrhenate with tin(II) chloride in 2N hydrochloric acid in the presence of excess alkylthiourea. The obtained compounds were [Re III (alkylthiourea-S) 6 ]X 3 . n H 2 O, where X is Cl − or PF 6 − and alkylthiourea is N -methylthiourea (Metu), N,N′-dimethylthiourea (Me 2 tu) or N -ethylthiourea (Ettu). Complexes were characterized by elemental and thermal analyses and by electronic and FTIR spectroscopy. Their kinetic stabilities in aqueous and methanolic solutions were also studied. Results were compared with those previously reported for [Re III (tu-S) 6 ]Cl 3 .4H 2 O, where tu=thiourea. Molecular structures of [Re III (Ettu) 6 ](PF 6 ) 3 and [Re III (Me 2 tu) 6 ](PF 6 ) 3 were determined by single crystal X-ray diffraction methods. The coordination polyhedra around the Re(III) ion are distorted octahedra. The six alkylthiourea ligands are sulfur bonded to the central atom [ d (Re–S) ranges from 2.402(4) to 2.441(4) A for the ethylthiourea complex and from 2.416(3) to 2.446(3) for the dimethylthiourea one]. Capability of working as starting materials via ligand substitution, in methanolic medium for these new Re(III) complexes and for previously reported [Re III (tu) 6 ]Cl 3 .4H 2 O is stated. Selected incoming ligands, 1,2-bis(diphenylphosphino) ethane (dppe) and 1,3-bis(diphenylphosphino) propane (dppp), lead to the already known [Re III (dppe) 2 Cl 2 ]Cl.2MeOH and [Re III (dppp) 2 Cl 2 ]Cl with good yields. Re(III) complexes with thiourea and alkylthioureas can be ordered according to their substitution rate as follows: [Re(tu) 6 ] 3+ 6 ] 3+ ≅[Re(Metu) 6 ] 3+ 2 tu) 6 ] 3+ .

[ReIII(thiourea‐S)6]Cl3 · 4 H2O and [ReIII(N‐methylthiourea‐S)6]Cl3 as Precursors to other ReIII Complexes: a Kinetic Study in Aqueous Media. Crystal Structure of [ReIII(N‐methylthiourea‐S)6](PF6)3 · H2O

Capability of [ReIII(tu-S)6]Cl3, where tu = thiourea, as a precursor to other ReIII complexes by ligand substitution in aqueous medium is studied. For the decomposition of [Re(tu-S)6]Cl3, experiments suggest pseudo first order kinetics and observed rate constants vary from 1.3 × 10–2 to 9.6 × 10–2 min–1 in the pH range 2.80–5.04. Experiments in presence of incoming ligand (ethylendiaminetetraacetic acid or diethylentriaminepentaacetic acid) show that ligand substitution is significantly slower than decomposition of the precursor, even when pH and temperature are modified. Similar results were obtained working with [ReIII(Metu-S)6]Cl3, where Metu = N-methylthiourea. Molecular structure of [ReIII(Metu-S)6](PF6)3 · H2O was determined by single crystal X-ray diffractometry. The coordination polyhedron around the Re ion is a distorted octahedron. The six methylthiourea ligands are bonded to the metal through the sulfur atoms [bond lengths range from 2.409(2) to 2.451(2) A]. [ReIII(thioharnstoff-S)6]Cl3 · 4 H2O und [ReIII(N-methylthioharnstoff-S)6]Cl3 als Vorlaufer fur andere ReIII-Komplexe: Eine kinetische Untersuchung in wasrigem Medium. Die Kristallstruktur von [ReIII(N-methylthioharnstoff-S)6](PF6)3 · H2O Es wird die Eignung von [ReIII(tu-S)6]Cl3 (tu = Thioharnstoff) als Vorlaufer fur andere ReIII-Komplexe durch Ligandenaustausch in wasrigem Medium untersucht. Die Dissoziation von [Re(tu-S)6]Cl3 zeigt im pH-Bereich von 2,80–5,04 eine Kinetik Pseudo-Erster-Ordnung mit einer Geschwindigkeitskonstanten im Bereich von 1,3 × 10–2 bis 9,6 × 10–2 min–1. Experimente im Beisein von Liganden (Ethylendiamin-Tetraessigsaure oder DiethylentriaminPentaessigsaure) zeigen auch bei Variation von Temperatur und pH-Wert eine signifikant langsamere Liganden-Substitution als es der Dissoziation des Vorlaufers entspricht. Ahnliche Ergebnisse werden mit [ReIII(Metu-S)6]Cl3 (Metu = N-Methylthioharnstoff) erzielt. Die Molekulstruktur von [ReIII(Metu-S)6](PF6)3 · H2O wird durch Einkristall-Rontgenstrukturanalyse ermittelt. Das Koordinationspolyeder am Re-Ion ist verzerrt oktaedrisch. Die sechs N-Methylthioharnstoff-Liganden sind uber die Schwefel-Atome an das Rhenium-Atom gebunden [Bindungslangen von 2,409(2) bis 2,451(2) A].

Exploring Oxidovanadium(IV) Complexes as YopH Inhibitors: Mechanism of Action and Modeling Studies.

YopH tyrosine phosphatase, a virulence factor produced by pathogenic species of Yersinia, is an attractive drug target. In this work, three oxidovanadium(IV) complexes were assayed against recombinant YopH and showed strong inhibition of the enzyme in the nanomolar range. Molecular modeling indicated that their binding is reinforced by H-bond, cation−π, and π–π interactions conferring specificity toward YopH. These complexes are thus interesting lead molecules for phosphatase inhibitor drug discovery.

Crystal Structure of trans- [ReCl2(dppp)2]Cl · ½H2O (dppp = 1,3-bis(diphenylphosphino)propane)

The crystal structure of trans-[ReCl2(dppp)2]- Cl · ½H2O (dppp = 1,3-bis(diphenylphosphino)- propane), a potentially useful radiopharmaceutical agent, was determined by single crystal X-ray diffractometry. It belongs to the tetragonal space group P4̄ with Z = 2. The Re(III) ion is in a quasioctahedral environment coordinated to a pair of symmetry related dppp molecules, acting as bidentate ligands, and two axial chloride ions.