Chiral Anticancer Ti(IV) Phenolato Complexes; About Stereochemistry and Mode of Action

Maya Miller maya.stolarov@mail.huji.ac.il 1 Emiliano Cohen 2 Ori Braitbard 3 Jacob Hochman 3 Yuval Tabach 2 Edit Y. Tshuva 1
1The Hebrew University of Jerusalem, Institute of Chemistry, Jerusalem, Israel
2The Hebrew University of Jerusalem, School of Medicine, Developmental Biology and Cancer Research, Jerusalem, Israel
3The Hebrew University of Jerusalem, Alexander Silberman Institute of Life Science, Jerusalem, Israel

Titanium anticancer complexes arose in 1980th with two leading compounds, titanocene dichloride and budotitane.1,2 Titanium is a biocompatible metal with a rich aquatic chemistry that eventually lead to failure in clinical trials. The identification of the active species as well as their mode of action in the biological environment are still enigmatic. The advanced titanium compounds based on phenolato ligands feature enhanced resistance to hydrolysis, and show high anti-tumor activity toward various cancer cell lines, selectivity to cancer tissue, durability in aquatic solutions and effectiveness in in vivo models.

This work aims to elaborate our understanding of the molecular mechanism involved in the activity of anticancer Ti(IV) phenolato complexes, and to identify the most active enantiomerically pure chiral compound. Since Ti(IV) phenolato complexes exhibit C2-symmetry, rendering them chiral, racemic as well as enantiomerically pure forms were synthesized through ligand to metal chiral induction.3 Their cytotoxicity and hydrolytic stability will be discussed. Biochemical studies were performed on a leading phenolato Ti(IV) compound showing; (a) influence on the cell cycle, causing G1 arrest; (b) upregulation of p53 and cleaved caspase9 proteins, implying an apoptotic pathways. Comparing cytotoxicity, cellular uptake, and protein levels in two cell lines imply that different mechanisms of action are plausible.4 To elaborate, gene expression using RNA-seq methodology was performed. Clustering the most variable genes, while using gene analytics tools, showed possible signaling involved in DNA and protein binding, influence on mitochondrial transduction, and eruption to cell cycle. Altogether, the preliminary mechanistic insights gained should advance these promising Ti(IV) phenolato complexes for the use in cancer treatment.

References:

  1. Tshuva E.Y.; Miller M; Chem.Mol.Sci. and Eng. (2017), doi.org/10.1016/B978-0-12-409547-2.13641-8.
  2. Tshuva E.Y.; Miller M; Met. Ions Life Sci., (2018), 18, in press
  3. Miller M. et al; Eur.J.Inorg.Chem. (2014) 9, 1485.
  4. Miller M. et al; J.Inorg.Biochem. (2016) 163, 250-257.








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