Ti<sup>IV</sup> Complexes of Branched Diamine Bis(phenolato) Ligands: Hydrolysis and Cytotoxicity

Peri, Dani; Manna, Cesar M.; Shavit, Michal; Tshuva, Edit Y.

doi:10.1002/ejic.201100725

Cited by 31 publications

(22 citation statements)

References 26 publications

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“…Among the transition metals tested, two titanium‐based complexes—budotitane and titanocene dichloride—reached clinical trials, but failed due to rapid hydrolysis and the formation of undefined aggregates . To overcome these obstacles, our laboratory developed a new family of titanium(IV) complexes based on phenolato ligands . In particular, diaminobis(phenolato)‐bis(alkoxo)Ti IV (phenolaTi, Figure ) demonstrated remarkable stability in aqueous media and an extended shelf life, along with enhanced in vitro cytotoxicity toward various cancer cell types .…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] To overcome these obstacles, our laboratory developed an ew family of titanium(IV) complexes based on phenolato ligands. [30][31][32][33][34][35][36][37][38][39][40][41][42] In particular,d iaminobis(phenolato)-bis(alkoxo)Ti IV (phenolaTi,F igure 1) demonstrated remarkable stability in aqueous media and an extended shelf life, along with enhanced in vitro cytotoxicity toward various cancer cell types. [43] In previous studies, the phenolaTic omplex also displayeds ynergistic or additive characteristics when combined in vitro with cisplatin or oxaliplatin, [44] and an antitumorigenic effect when tested in vivoi nm ice inoculated with lymphoma growinga s ascites.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

et al. 2018

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Due to the toxicity of platinum compounds used in the clinic as anticancer chemotherapies, titanium serves as a safe and attractive alternative. Lately, we introduced a new family of Ti complexes based on readily available phenolato ligands, demonstrating incredibly high hydrolytic stability, with the lead compound phenolaTi demonstrating wide cytotoxic activity toward the NCI‐60 panel of human cancer cell lines, with an average GI50 value of 4.7±2 μm. Herein, we evaluated in vivo: a) the safety, and b) the growth inhibitory capacity (efficacy) of this compound. PhenolaTi was found to be effective in vivo against colon (CT‐26) and lung (LLC‐1) murine cell lines in syngeneic hosts and toward a human colon cancer (HT‐29) cell line in immune‐deficient (Nude) mice, with an efficacy similar to that of known chemotherapy. Notably, no clinical signs of toxicity were observed in the treated mice, namely, no effect on body weight, spleen weight or kidney function, unlike the effects observed with the positive control Pt drugs. Studies of combinations of phenolaTi and Pt drugs provided evidence that similar efficacy with decreased toxicity may be achieved, which is highly valuable for medicinal applications.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

et al. 2018

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“…Since then, the rapid hydrolysis of Ti(IV) complexes has been an obstacle in utilizing them as potential anti-tumor drugs. Nevertheless, we introduced a third family of cytotoxic Ti(IV) agents that is based on phenolato ligands [24,25,26,27,28,29,30]. Complexes of this type demonstrate high in vitro activity toward various cancer cell-lines, in vivo efficacy, and markedly improved hydrolytic stability compared with budotitane and titanocene dichloride [31,32].…”

Section: Introductionmentioning

confidence: 99%

Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity

et al. 2015

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Titanium(IV) complexes exhibit high potential as anti-tumor agents, particularly due to their low intrinsic toxicity and cytotoxicity toward cisplatin resistant cells. Nevertheless, Ti(IV) complexes generally undergo rapid hydrolysis that previously hampered their utilization as anticancer drugs. We recently overcame this difficulty by developing a highly stable Ti(IV) complex that is based on tetra-phenolato, hexadentate ligand, formulated into organic nanoparticles. Herein we investigated the activity of this complex in vitro and in vivo. Although inactive when tested directly due to poor solubility, when formulated, this complex displayed (a) high cytotoxicity toward cisplatin resistant human ovarian cells, A2780-cp, with resistance factor of 1.1; (b) additive behavior in combination with cisplatin toward ovarian and colon cancer cells; (c) selectivity toward cancer cells as implied by its mild activity toward non-cancerous, fibroblast lung cells, MRC-5; (d) high stability and durability as manifested by the ability to maintain cytotoxicity, even following one week of incubation in 100% aquatic medium solution; and (e) in vivo efficacy toward solid tumors of human colon cancer cells, HT-29, in nude mice without any OPEN ACCESSMolecules 2015, 20 18527 clinical signs of toxicity. These features support the formulated phenolato Ti(IV) complex being an effective and selective anti-tumoral agent.

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“…Lactide (Aldrich) was recrystallized with dry toluene and then sublimed twice under vacuum at 80°C. L 2 H and (L 2 )Ti(O i Pr) 2 were prepared following literature procedures . All other chemicals were purchased from Aladdin (China) and used after appropriate purification.…”

Section: Methodsmentioning

confidence: 99%

Titanium complexes bearing amine bis(phenolate) ligands: Synthesis, structure and catalysis in ring‐opening polymerization of lactide

Wang

Zhang

Zhao

et al. 2016

Applied Organom Chemis

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= Me, R 4 = OMe, R 5 = t Bu, (L 5 )Ti(O i Pr) 2 ) supported by amine bis(phenolate) ligands were synthesized and characterized using NMR spectroscopy and elemental analysis. The solid-state structure of (L 3 )Ti(O i Pr) 2 was determined using single-crystal X-ray diffraction. (L 1-5 )Ti(O i Pr) 2 were all found to initiate the ring-opening polymerization of L-lactide and rac-lactide in a controlled manner at 110-160°C. As shown by kinetic studies, (L 1 )Ti(O i Pr) 2 polymerized L-lactide faster than did (L 2-5 )Ti(O i Pr) 2 . In addition, good number-average molecular weight and narrow polydispersity index (1.00-1.71) of polymers were also obtained. The microstructure of the polymers and a possible mechanism of coordination-insertion of polymerization were evidenced by MALDI-TOF and 1 H NMR spectra of the polylactides. KEYWORDS amine bis(phenolate) ligands, ring-opening polymerization of lactide, titanium complexes

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Ti^IV Complexes of Branched Diamine Bis(phenolato) Ligands: Hydrolysis and Cytotoxicity

Cited by 31 publications

References 26 publications

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity

Titanium complexes bearing amine bis(phenolate) ligands: Synthesis, structure and catalysis in ring‐opening polymerization of lactide

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TiIV Complexes of Branched Diamine Bis(phenolato) Ligands: Hydrolysis and Cytotoxicity

Cited by 31 publications

References 26 publications

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity

Titanium complexes bearing amine bis(phenolate) ligands: Synthesis, structure and catalysis in ring‐opening polymerization of lactide

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Product

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Ti^IV Complexes of Branched Diamine Bis(phenolato) Ligands: Hydrolysis and Cytotoxicity