Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible, Effective and Selective Anticancer Agents

Sigalit Meker, Ori Braitbard, Matthew D. Hall, Jacob Hochman, Edit Y. Tshuva*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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 GI50of 4.6±2 μm. This newly developed family of TiIVcomplexes is thus of great potential for anticancer therapy.

Original languageAmerican English
Pages (from-to)9986-9995
Number of pages10
JournalChemistry - A European Journal
Volume22
Issue number29
DOIs
StatePublished - 11 Jul 2016

Bibliographical note

Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • N,O ligands
  • antitumor agents
  • drug design
  • ligand design
  • titanium

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