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The activity of amine bis(phenolate) Ti dibenzyl complexes in 1-hexene polymerization catalysis as a function of the phenolate substituents was investigated. Two series of Ti complexes carrying either a dimethylamino or a methoxy sidearm donor were prepared and characterized. In each series, the substituents on the phenolate rings were either alkyl groups of varying bulk or electron-withdrawing chloro groups. When activated with a suitable Lewis acid, all precatalysts have shown reactivity toward 1-hexene. Different structure-activity trends were observed in the two series: The activity of the catalysts of the “OMe” series was low to moderate and was almost independent of the phenolate substituents. In contrast, the activity of the “NMe2” catalysts had a strong dependence on both the steric and electronic character of the phenolate substituents, ranging from mild to highly active. The difference in polymerization activity trends between the two series may be traced back to their different tendency toward misinsertions. A “NMe2”-Ti complex having Cl groups in the ortho, para positions of the phenolate rings led to the most active catalyst and to a remarkably high-Mw polymer (>4 000 000) obtained withi n1ho fpolymerization at RT. The characterization of this ultrahigh-Mw atactic poly(1-hexene) by means of oscillatory rheometry and stress relaxation experiments indicated typical elastomeric behavior at RT.

The catalytic oxidation of triphenylphosphine in the presence of dioxygen by the diiron(II) complex [Fe(2)(micro-O(2)CAr(Tol))(2)(Me(3)TACN)(2)(MeCN)(2)](OTf)(2) (1), where (-)O(2)CAr(Tol) = 2,6-di(p-tolyl)benzoate and Me(3)TACN = 1,4,7-trimethyl-1,4,7-triazacyclononane, has been investigated. The corresponding diiron(III) complex, [Fe(2)(micro-O)(micro-O(2)CAr(Tol))(2)(Me(3)TACN)(2)](OTf)(2) (2), the only detectable iron-containing species during the course of the reaction, can itself promote the reaction. Phosphine oxidation is coupled to the catalytic oxidation of THF solvent to afford, selectively, the C-C bond-cleavage product 3-hydroxypropylformate, an unprecedented transformation. After consumption of the phosphine, solvent oxidation continues but results in the products 2-hydroperoxytetrahydrofuran, butyrolactone, and butyrolactol. The similarities of the reaction pathways observed in the presence and absence of catalyst, as well as (18)O labeling, solvent dependence, and radical probe experiments, provide evidence that the oxidation is initiated by a metal-centered H-atom abstraction from THF. A mechanism for catalysis is proposed that accounts for the coupled oxidation of the phosphine and the THF ring-opening reaction.

The polymerization of propylene employing the recently developed amine bis(phenolate) zirconium catalysts is reported for the first time. The polymerizations were conducted in liquid propylene employing two different experimental setups, and two different precatalysts, based on the same amine bis(phenolate) ligand having a dimethylamino donor on a sidearm. The first precatalyst studied was a dibenzyl zirconium complex, which was found to lead to high molecular weight atactic polypropylene. The effects of the cocatalyst, the ratio between the cocatalyst and the precatalyst, and the polymerization temperature on the nature of the resulting polymer and the activity of the catalyst were studied. Reducing the relative amount of the cocatalyst and lowering the polymerization temperature increased the molecular weight of the polymer, and a temperature of 50 °C led to the most active catalyst. A dichloro zirconium complex of the same ligand, expected to show a higher hydrolytic and thermal stability was developed, its X-ray structure was solved, and its activity in polymerization of propylene was studied and found to be similar to that of the dibenzyl precatalyst.

Several [ONXO]-type zirconium and hafnium dibenzyl complexes of amine bis(phenolate) ligands, where X is a heteroatom donor located on a pendant arm, were synthesized directly from the ligand precursors and the corresponding tetrabenzylmetal complexes in quantitative yields (X = N, O, S). All complexes exhibited remarkable activities in the polymerization of 1-hexene, yielding high-molecular-weight polymers, the highest activity being unprecedented under the conditions employed. An unexpected metal-dependent activity pattern was demonstrated. The high activity of the complexes is derived from the binding of the side-arm donor to the metal and is affected by its nature. The activity order of the zirconium complexes as a function of the side-arm donor was found to be OMe > NMe2 > SMe (5:2:1). The X-ray structures of all zirconium complexes were solved and revealed very similar binding of the [ONO] ligand cores to the metal. The distances between the side-arm donor atoms and the zirconium are relatively long...

Salan titanium(IV) complexes of differently substituted aromatic rings, where one ring is para-nitrated and another is ortho,para-halogenated, demonstrate exceptionally high anticancer activity, with IC(50) values of1 μM, exceeding that of cisplatin by ~30-fold. Whereas an additive effect in hydrolytic stability was detected for these highly stable complexes, an unexpected synergistic effect in anticancer activity makes these hybrid complexes substantially more active than both their symmetrical analogues alone and their equimolar mixture.

The first NMR structure of a Cu(I)-bound metallochaperone model with the conserved sequence MT/HCXXC revealed that at pH similar to 3.0 and similar to 6.8 Cu(I) binds through one Cys and the Met rather than the two Cys residues, differently than at pH similar to 8.5. This suggests a possible role of Met in metal transport.

Copper (I) binding by metallochaperone transport proteins prevents copper oxidation and release of the toxic ions that may participate in harmful redox reactions. The Cu (I) complex of the peptide model of a Cu (I) binding metallochaperone protein, which includes the sequence MTCSGCSRPG (underlined is conserved), was determined in solution under inert conditions by NMR spectroscopy. NMR is a widely accepted technique for the determination of solution structures of proteins and peptides. Due to difficulty in crystallization to provide single crystals suitable for X-ray crystallography, the NMR technique is extremely valuable, especially as it provides information on the solution state rather than the solid state. Herein we describe all steps that are required for full three-dimensional structure determinations by NMR. The protocol includes sample preparation in an NMR tube, 1D and 2D data collection and processing, peak assignment and integration, molecular mechanics calculations, and structure analysis. Importantly, the analysis was first conducted without any preset metal-ligand bonds, to assure a reliable structure determination in an unbiased manner.

The coordination chemistry of titanium(IV) complexes of amine bis(phenolate) ligands was investigated by synthesizing various types of complexes and analyzing them specroscopically and structurally. Steric effects of tridentate [ONO]- and tetradentate [ONNO]-type ligands were studied by reacting the ligand precursors with titanium tetra(isopropoxide). [ONNO]-type ligands featuring an amine donor located on a pendant arm led to octahedral bis(isopropoxide) complexes, regardless of the steric bulk around the metal. Several such complexes having varying steric crowding were thus synthesized. On the other hand, steric effects were found to play a major role in determining the complex constitution when [ONO]-type ligands, featuring no side donor, were involved. Relatively sterically undemanding ligands led to octahedral bis(homoleptic) complexes, whereas increased steric bulk resulted in the formation of pentacoordinate bis(isopropoxide) complexes. These pentacoordinate complexes readily lead to bis(heteroleptic) complexes by reaction with nonsterically demanding [ONO]- and [ONNO]-type ligand precursors. In the latter case the sidearm nitrogen remains uncoordinated to the metal. The bis(isopropoxide) complexes of the [ONNO]-type ligands may also lead to bis(heteroleptic) complexes, however, these reactions are much slower.

Novel amine bis(phenolate) zirconium dibenzyl complexes were synthesized in quantitative yields from a versatile family of chelating amine−bis((2-hydroxyaryl)methyl) ligand precursors, their X-ray structures solved, and their reactivity in the polymerization of 1-hexene in the presence of B(C6F5)3 studied. Several minor peripheral structural modifications were studied and found to have a major influence on the catalyst performance. Thus, a variety of reactivities, ranging from extremely high to negligible, were obtained, demonstrating a unique structure−reactivity relationship. This relationship is partially revealed from the crystal structures of the precatalysts, indicating similar [ONO] ligand cores in all structures solved. A correlation between the solid and the solution structures is obtained from 1H NMR spectra, which reveal a rigid binding of the ligand to the metal. The solid structures are therefore proposed to serve as reliable references when studying structure−reactivity relationships. The mo...

Two amine bis(phenolate) titanium dibenzyl complexes were synthesized in one-pot reactions starting from the ligand precursors and titanium tetra(isopropoxide). The catalyst derived from a ligand having an extra donor on a side arm leads to living polymerization of 1-hexene at room temperature, whereas the one derived from a ligand lacking it, leads to low molecular weight poly(1-hexene) with PDI values of around 2.0.

Copper (I) binding by metallochaperone transport proteins prevents copper oxidation and release of the toxic ions that may participate in harmful redox reactions. The Cu (I) complex of the peptide model of a Cu (I) binding metallochaperone protein, which includes the sequence MTCSGCSRPG (underlined is conserved), was determined in solution under inert conditions by NMR spectroscopy. NMR is a widely accepted technique for the determination of solution structures of proteins and peptides. Due to difficulty in crystallization to provide single crystals suitable for X-ray crystallography, the NMR technique is extremely valuable, especially as it provides information on the solution state rather than the solid state. Herein we describe all steps that are required for full three-dimensional structure determinations by NMR. The protocol includes sample preparation in an NMR tube, 1D and 2D data collection and processing, peak assignment and integration, molecular mechanics calculations, and structure analysis. Importantly, the analysis was first conducted without any preset metal-ligand bonds, to assure a reliable structure determination in an unbiased manner.

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay. The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity. Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values.

In this paper we report the synthesis and full characterisation of a range of Ti(IV)-catecholato systems complexed to piperazine or homopiperazine salan ligands. The steric/electronic environment of the catecholate moiety has been varied and the effect this has on cytotoxicity discussed. It was observed that the 7-membered homopiperazine complexes are more stable to hydrolysis than their piperazine cousins in biological media. In general the homopiperazine complexes show higher cytotoxicity than the piperazine complexes, with the most cytotoxic complex exhibiting IC50 (μM) values of 3 ± 0.5 μM (HT-29) and 4 ± 1 μM (OVCAR).

Titanium(IV) complexes with a salan or cyclopentadienyl ligand showed different biological behaviour concerning binding to biomolecules, cellular accumulation and intracellular distribution. Binding efficacy as well as trafficking on the cellular level are crucial parameters for their biological effects.

The first NMR structures of Cu(I) and Zn(II) peptide complexes as models of metallochaperones were derived with no predetermined binding mode. The cyclic peptide MDCSGCSRPG was reacted with Cu(I) and Zn(II) at low and moderate pH. This peptide features the conserved sequence of copper chaperones but with Asp at position 2 as appears in the zinc binding domain of ZntA. The structures were compared with those of the Cu(I) complexes of the wild-type sequence peptide MTCSGCSRPG. All analyses were conducted first with no metal-binding constraints to ensure accurate binding ligand assignment. Several structures included metal-Met binding, raising a possible role of Met in the metal transport mechanism. Both Cu(I) and Zn(II) gave different complexes when reacted with the peptide of the native-like sequence under different pH conditions, raising the possibility of pH-dependent transport mechanisms. Cu(I) bound the MTCSGCSRPG peptide through one Cys and the Met under acidic conditions and differently under basic conditions; Zn(II) bound the MDCSGCSRPG peptide through two Cys and the Met residues under acidic conditions and through one Cys and the Met under basic conditions, while Cu(I) bound the non-native Asp mutant peptide through the Asp and one Cys under both conditions, suggesting that Asp may inhibit pH-dependent binding for Cu(I). NOESY and ESI-HRMS supported the presence of an aqua ligand for Zn(II), which likely deprotonated under basic conditions to give a hydroxo group. Coordination similarities were detected among the model system and native proteins, which overall suggest that coordination flexibility is required for the function of metallochaperones.

Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24-48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI-60 panel, with average GI50 of 4.6±2 μm. This newly developed family of Ti(IV) complexes is thus of great potential for anticancer therapy.

Vanadium(V) oxo complexes with tetradentate diamine bis(phenolato) "salan" ligands of the type LVO(OiPr) (L is salan) with different steric and electronic substitutions at the ortho and para positions to the binding phenolato moiety were synthesized and their hydrolytic stability and cytotoxicity were analyzed. With one exception bearing large steric groups, all complexes examined displayed marked cytotoxic activity, comparable to, and often higher than, that of cisplatin. While the hydrolytic stability changed significantly depending on the substituent at the ortho position relative the O-donor with little effect of para substitutions, the cytotoxic activity largely was not affected, and high cytotoxicity was recorded also for relatively unstable complexes. Additional measurements revealed that the cytotoxicity is largely maintained following pre-incubation of up to 18 hours of the complexes in the biological medium prior to cell addition, suggesting that hydrolysis products might serve as the active species. In addition, appreciable cytotoxic activity was measured for an isolated hydrolysis product that was analyzed crystallographically to exhibit a dimeric structure with bridging oxo ligand where both metal centers are bound to the salan ligand, supporting the aforementioned conclusions.

Transition metal ions can be both beneficial and harmful to biological systems if not carefully regulated. A family of proteins that include a conserved sequence in their binding site of MXCXXC is responsible for delivery and homeostasis of different metals. Model studies present an effective tool for studying the parameters governing metal affinity, selectivity and other mechanistic aspects. Small-molecule, peptide-based, and advanced models will be presented, as well as functional models of potential industrial applications.

Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic agents. We have recently introduced the highly efficient C(2)-symmetrical salan-Ti(IV) family of complexes, demonstrating high cytotoxicity toward colon and ovarian cells and enhanced hydrolytic stability in mixed organic/water solutions. The effect of stereochemistry is hereby reported, by comparing the cytotoxic activity and hydrolysis of pure enantiomers and their racemic mixture for four complexes of this family with different aromatic substitutions: para-Me, para-Cl, ortho-Cl, and ortho-OMe. These complexes include the trans-diaminocyclohexyl bridge, which enables ligand-to-metal chiral induction to give solely the Δ isomer when starting from the R,R ligand and vice versa. Different activity is obtained for the different stereochemical forms (Δ, Λ, and rac) in two of the four complexes, where for the other two either all forms are inactive or all are highly active. Additionally, where not all are of similar activity, the racemic mixture is the least active of the three. We therefore conclude that the salan ligand is essential for the fruitful biological interaction, which probably involves a chiral cellular target. The activity of the racemate differing from that expected from a simple mixture of enantiomers operating separately may be explained by the involvement of a polynuclear active species, where different metal centers might be of different configurations. This is particularly supported by the different polynuclear products of hydrolysis obtained from an optically pure complex and from the racemic one, as analyzed crystallographically. The former is an all-R,R chiral C(1)-symmetrical homodimer, while the latter is an achiral R,R-S,SC(i)-symmetrical heterodimer obtained through chiral recognition.

Six TiIV complexes of branched diamine bis(phenolato) ligands that feature a pendant donor side arm with different aromatic and N-substitutions were synthesized and their hydrolytic stability and cytotoxicity were investigated as closely related analogues to the highly active and stable salan TiIV complexes [salan = N,N′-bis(o-hydroxybenzyl)-1,2-diaminoethane]. Although the Cs-symmetrical complexes include binding of the side-arm N donor to the metal as analyzed crystallographically, thus making them highly similar in coordination features to the C2-symmetrical salan complexes, they exhibit poor hydrolytic stability, presumably due to higher flexibility in binding of the side arm in solution. Complexes of alkyl aromatic substituents, both N-methylated and N-ethylated, with varying steric constraints demonstrated poor cytotoxicity. In contrast, ortho-halogenation, although it does not affect hydrolytic stability, substantially enhances the cytotoxicity towards colon HT-29 and ovarian OVCAR-1 cells.

Salen-titanium(IV) complexes are introduced as a new family of highly efficient antitumor complexes, being the first cytotoxic titanium(IV) complexes of trans labile ligands, as characterized crystallographically. Four complexes with different aromatic substitutions were analyzed, reveling a meaningful effect of the ligand structure on the complex performance. All complexes exhibit high hydrolytic stability, where the labile OAr ligands hydrolyze in a 10% D(2)O solution with t(1/2) ranging from 2 to 11 h. The IC(50) values obtained for three of the salen complexes studied on HT-29 colon and OVCAR-1 ovarian cells demonstrate activity that exceeds those of the known tianium(IV) complexes Cp(2)TiCl(2) and (bzac)(2)Ti(OiPr)(2) and that of cisplatin, where the most active para-chlorinated complex exhibits activity enhancement relative to cisplatin by 10-fold.

Bis(isopropoxo) Ti(IV) complexes of diamino bis(phenolato) "salan" ligands were prepared, their hydrolysis in 1:9 water/THF solutions was investigated, and their cytotoxicity toward colon HT-29 and ovarian OVCAR-1 cells was measured. In particular, electronic effects at positions ortho and para to the binding phenolato unit were analyzed. We found that para substituents of different electronic features, including Me, Cl, OMe, and NO(2), have very little influence on hydrolysis rate, and all para-substituted ortho-H complexes hydrolyze slowly to give O-bridged clusters with a t(1/2) of 1-2 h for isopropoxo release. Consequently, no clear cytotoxicity pattern is observed as well, where the largest influence of para substituents appears to be of a steric nature. These complexes exhibit IC(50) values of 2-18 μM toward the cells analyzed, with activity which is mostly higher than those of Cp(2)TiCl(2), (bzac)(2)Ti(OiPr)(2) and cisplatin. On the contrary, major electronic effects are observed for substituents at the ortho position, with an influence that exceeds even that of steric hindrance. Ortho-chloro or -bromo substituted compounds possess extremely high hydrolytic stability where no major isopropoxo release as isopropanol occurs for days. In accordance, very high cytotoxicity toward colon and ovarian cells is observed for ortho-Cl and -Br complexes, with IC(50) values of 1-8 μM, where the most cytotoxic complexes are the ortho-Cl-para-Me and ortho-Br-para-Me derivatives. In this series of ortho-substituted complexes, the halogen radius is of lesser influence both on hydrolysis and on cytotoxicity, while OMe substituents do not impose similar effect of hydrolytic stability and cytotoxicity enhancement. Therefore, hydrolytic stability and cytotoxic activity are clearly intertwined, and thus this family of readily available Ti(IV) salan complexes exhibiting both features in an enhanced manner is highly attractive for further exploration.

A convenient route for the synthesis of a variety of salan-type compounds is introduced. The synthesis is based on a single-step Mannich condensation between readily available starting materials: primary or secondary amines, formaldehyde and substituted phenols. This methodology is suitable for the preparation of chiral salans as well, which may find applications in asymmetric catalysis.

The two enantiomers of a member of the highly active C(2)-symmetrical bis(isopropoxo) Ti(iv) family of complexes of diamine bis(phenolato) ligands demonstrate markedly different cytotoxicity, supporting a chiral biological target of activity and participation of a ligand-bound active species.

In this paper we overview our studies on amine–phenolato TiIV complexes as cytotoxic agents, in the context of the results reported thus far with titanocene dichloride, budotitane and derivatives. In particular, we emphasize the studies about the structure–activity relationship performed and important insights gained with the known compounds and our complexes, in regards to their hydrolytic behavior and cytotoxic activity, while pointing to potential mechanistic aspects. Titanocene dichloride and budotitane show cytotoxic activity towards cells that are resistant to cisplatin with reduced side effects. Their main drawback is their hydrolytic instability that has impeded mechanistic investigations and pharmaceutical use. Our new family of cytotoxic complexes was designed to include a single highly electron-donating chelating ligand to afford octahedral TiIV complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. The effect of several parameters on hydrolysis and cytotoxicity were investigated, including those relating to the tetradentate ligand and those relating to the labile groups. Overall we observed high cytotoxic activity that is strongly dependent on the ligand, and which is strongly correlated to the complex hydrolytic behavior. Additional mechanistic studies provide insights regarding the time frame of activity and cell penetration. Some comparisons to titanocene dichloride, budotitane and analogues are highlighted.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Carefully design your ligand! A new family of highly cytotoxic TiIV complexes demonstrates strong dependence of activity on the particular ligand employed, in which small structural modifications dramatically affect both hydrolytic behavior and biological activity (see picture). Different structure-dependence patterns are observed for hydrolysis and cytotoxicity, which are, nonetheless, strongly related. We recently introduced a new class of bis(isopropoxo)–TiIV complexes with diamine bis(phenolato) ligands that possess antitumor activity against colon HT-29 and ovarian OVCAR-1 cells that is higher than that of the known TiIV compounds titanocene dichloride and budotitane as well as that of cisplatin. Herein, we elaborate on this family of compounds; we discuss the effect of structural parameters on the cytotoxic activity and hydrolytic behavior of these complexes, seeking a relationship between the two. Whereas complexes with small steric groups around the metal center possess high activity and lead mostly to formation of O-bridged polynuclear complexes with bound bis(phenolato) ligand upon water addition, bulky complexes hydrolyze to release all free ligands and are inactive. Slightly increasing the size of the N-donor substituents probably weakens the ligand binding in solution, and, thus, rapid hydrolysis is observed, leading to a lack of cytotoxicity, supporting the requirement for ligand inertness. Replacing the two isopropoxo ligands with a single catecholato unit gives a complex with a different geometry that exhibits slower hydrolysis and reduced cytotoxicity, suggesting some participation of labile ligand hydrolysis in the cytotoxicity mechanism. A crystallographically characterized O-bridged polynuclear species obtained from a biologically active bis(isopropoxo) complex upon water addition is inactive, which rules out its participation as the active species, yet suggests some role of the particular steric and electronic requirements allowing its formation in the activity mechanism. Additional measurements support rapid formation of the active species in the presence of cells prior to O-bridged TiIV cluster formation.

Two dianionic amine bis(phenolate) ligands are introduced and their reactions with titanium tetra(iso-propoxide) studied; ligand 1 having a single N-donor group leads exclusively to a homoleptic Lig2Ti type complex whereas ligand 3 having an additional N-donor on a side arm leads exclusively to a LigTi(OPri)2 type complex.

The synthesis of a sterically hindered di(mu-carboxylato)diiron(II) complex bearing terminal N,N',N"-trimethyl-1,4,7-triazacyclononane (Me(3)TACN) ligands and its reaction with dioxygen to afford a (mu-oxo)di(mu-carboxylato)diiron(III) complex are described. Both compounds initiate catalytic oxo transfer with O(2) as the terminal oxidant, converting phosphines to phosphine oxides, dimethyl sulfide to dimethyl sulfoxide, and dibenzylamine to benzaldehyde. Triphenylphosphine is oxidized to triphenylphosphine oxide with a turnover number of >2000 mol.P/mol.cat.

A new family of non-Cp-based non-diketonato-based C2-symmetrical octahedral Ti(IV) complexes of dianionic diamine bis(phenolato) ligands, which are conveniently obtained as single isomers in quanti...

Early attempts at using titanium compounds (derivatives of titanocene dichloride and budotitane) as anti-cancer treatment were essentially unsuccessful. The main reason was their rapid hydrolysis in biological media, leading to a variety of unidentified products that hampered the elucidation of mechanistic aspects. Lately, we have introduced a new class of Ti(IV) complexes of salan type diamino bis(phenolato) ligands. These compounds demonstrate substantially enhanced hydrolytic stability, as well as cytotoxic activity towards a variety of cancer cell lines in vitro. The IC50 of different derivatives of these compounds towards murine mammary carcinoma, lymphoma, multi-drug resistant lymphoma, as well as human leukemia, melanoma and pancreatic cancer cell lines, is in the range of 0.6 - 5.7μM, as compared to 70-100μM of the older titanium compounds and to 50-60μM of cisplatin (Manna C.M. et al. ChemMedChem, 7, 703 (2012)). Exposure of murine T-69 and human OVCAR-1 and HT-29 cell lines to one of the salan Ti(IV) compounds resulted in increased levels of p53 and growth arrest in G-1 of the cell cycle implying activation of the apoptotic pathway in response to Ti(IV) complexes.The well-identified and highly stable hydrolysis products of the titanium compounds, which had previously been formulated into nanoparticles to enhance solubility and assist cellular penetration (Meker, S. et al. Angew. Chem. Int. Ed. 51,10515 (2012)), were active both in vitro (IC50 -0.45μM) in murine lymphoma and in vivo (50% tumor growth inhibition) of the same lymphoma cells following their introduction into syngeneic mice. These findings suggest the potential use of solubilized active titanium compound derivatives as a new class of anti-cancer agents. Citation Format: Ori Braitbard, Sigalit Meker, Maya Stolarov, Jacob Hochman, Edit Tshuva. ‘Salan’ titanium(IV) complexes: A new class of anti-cancer agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2013-5496

Cisplatin is a widely used platinum-based metallo-chemotherapeutic drug that is considered an efficient treatment mainly for testicular and ovarian cancers. However, its narrow activity range and severe side effects trigger studies of other potent transition metal complexes. Two titanium(IV) anti-cancer agents that have been previously studied extensively as cisplatin alternatives are titanocene dichloride and budotitane. Despite their high activity, these complexes failed clinical trials mainly due to their poor water stability and formation of unidentified aggregates in water solutions. Our research group focuses on development of new, better-suited families of anti-tumor Ti(IV) complexes lacking Cp or diketonato ligands, and their investigation as anti-tumor agents. We recently reported the synthesis, characterization, and cytotoxicity of “salan” type Ti(IV) complexes [1]. The well defined hydrolytic behaviour, high stability, and high cytotoxicity of these compounds are strongly correlated to their particular structure. This enables fine tuning of complex properties by structural modifications. Herein we elaborate on the investigation of these salan titanium(IV) compounds. The correlation between the complex properties: structure, hydrolytic stability and cytotoxicity will be discussed, revealing insights on the biological mechanism of their cytotoxicity, suggesting an apoptotic cell death pathway.Additionally, further biological evaluation is presented, evincing that these compounds are markedly more active than cisplatin towards human and murine cancer-derived cell lines, including colon, ovarian, lung, cervix, pancreas, leukaemia, skin and breast, with activity also against cisplatin-resistant and multi-drug-resistant cells, and with minor effect on primary murine cells. In vivo experiments are now under way to determine both safety, as well as the anti-cancer activity of these complexes. [1] D. Peri, S. Meker, C. M. Manna, E. Y. Tshuva, Inorg. Chem., 2011, 50, 1030. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1762. doi:1538-7445.AM2012-1762

A series of Ti(IV) complexes containing diamino bis(phenolato) "salan" type ligands with NH coordination were prepared, and their hydrolysis and cytotoxicity were analyzed and compared to the N-methylated analogues. Substituting methyl groups on the coordinative nitrogen donor of highly active and stable Ti(IV) salan complexes with H atoms has two main consequences: the hydrolysis rate increases and the cytotoxic activity diminishes. In addition, the small modification of a single replacement of Me with H leads to a different major hydrolysis product, where a dinuclear Ti(IV) complex with two bridging oxo ligands is obtained, as characterized by X-ray crystallography, rather than a trinuclear cluster. A partial hydrolysis product containing a single oxo bridge was also crystallographically analyzed. Investigation of a series of complexes with NH donors of different steric and electronic effects revealed that cytotoxicity may be restored by fine tuning these parameters even for complexes of low stability.

Transition metal ions can be both beneficial and harmful to biological systems if not carefully regulated. A family of proteins that include a conserved sequence in their binding site of MXCXXC is responsible for delivery and homeostasis of different metals. Model studies present an effective tool for studying the parameters governing metal affinity, selectivity and other mechanistic aspects. Small-molecule, peptide-based, and advanced models will be presented, as well as functional models of potential industrial applications.

An amine bis(phenolate) dibenzyl titanium complex having a methoxy donor on a side arm leads, upon activation with tris(pentafluorophenyl)borane, to unique living properties in α-olefin polymerization: exceptionally high molecular weight poly(1-hexene) is obtained in a living fashion at room temperature, living polymerization of 1-hexene is obtained above room temperature, and block copolymerization of 1-hexene and 1-octene at room temperature is described as well.

Three bis(homoleptic) titanium complexes of hydroxyamino-1,3,5-triazine ligands 3a–c were synthesized and characterized, and their kinetic behavior in THF–water solutions was studied at various pH conditions using UV-vis, based on the characteristic Ti–O band at 380 nm. One of these complexes, 3c, was analyzed by X-ray crystallography. Due to the characteristic electronic structure of the triazine rings, high electron density on the nitrogen atoms leads to strong N–Ti bonds, as indicative by the 2.0 A coordinative bond lengths in the X-ray structure. Consequently, these complexes exhibit high hydrolytic stability over a wide pH range, where hydrolysis was observed to be promoted by basic conditions. At neutral pH, t1/2 was estimated to be >200 h, whereas at pH = 5.5, no hydrolysis was observed for a period of at least three days.