ABSTRACT
A new family of six mononuclear indium(III) complexes of formula mer-[InIIICl3(pz*H)3]-pz*H = pyrazole (pzH), or substituted pyrazoles: 4-Cl-pzH, 4-Br-pzH, 4-I-pzH, 4-Ph-pzH and 3,5-Me2-pzH-were synthesized by addition reactions of InCl3 and pz*H and crystallographically characterized. The fluxional behaviour of the complexes, probed by variable temperature 1H NMR spectroscopy in the 328 K to 173 K range, was attributed to (at least) four simultaneous processes: pyrazole N-H proton dissociation/association, cis/trans-pyrazole exchange, and N1/N2 tautomerization of the cis- and of the trans-pyrazoles. Three novel trianionic hexanuclear complexes of general formula (pipH)3[In6Cl6(µ3-OH0.5)2(µ-OH)6(µ-pz*)6]-pz* = pz, 4-Cl-pz and 4-Ph-pz-showing µ-hydroxo and µ-oxo bridges were synthesized from the corresponding mer-[InIIICl3(pz*H)3] and characterized by single crystal X-ray diffraction and 1H NMR. Under different solvent conditions, multicolour emitting polymeric complexes of general formula [In(µ-pz*)3]n-pz* = pz, 4-Cl-pz, 4-I-pz and 4-Ph-pz-were obtained also from mer-[InIIICl3(pz*H)3] after addition of a base. Luminescence and lifetime calculations were performed for all polymers formed.
ABSTRACT
The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2-, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV-vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2- transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis.
Subject(s)
Antineoplastic Agents/pharmacology , Benzoates/pharmacology , Coordination Complexes/pharmacology , Iron Chelating Agents/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzoates/chemical synthesis , Benzoates/chemistry , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Deferasirox , Drug Design , Drug Stability , Humans , Iron/chemistry , Iron Chelating Agents/chemical synthesis , Iron Chelating Agents/chemistry , Ligands , Models, Chemical , Molecular Structure , Serum Albumin/chemistry , Titanium/chemistry , Transferrin/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
The structure of the title compound, [Fe(C5H5)(C15H13O2)], consists of a ferrocenyl moiety and a 2-meth-oxy-phenyl group linked through a prop-2-en-1-one spacer in an E conformation. In the ferrocene unit, the substituted cyclo-penta-dienyl (Cps) ring and the unsubstituted cyclo-penta-dienyl ring (Cp) are almost parallel to one another [dihedral angle = 1.78â (14)°], and the Cp and Cps rings are in a gauche conformation. The benzene ring is twisted by 10.02â (14) and 11.38â (11)° with respect to the Cp and Cps rings, respectively. In the crystal, mol-ecules are linked by weak C-Hâ¯O hydrogen bonds into supra-molecular chains running along the b-axis direction.
