Oxali‐Titanocene Y: A Potent Anticancer Drug

Synthesis, Characterization, Cytotoxicity, and Hydrolytic Behavior of C2‐ and C1‐Symmetrical TiIV Complexes of Tetradentate Diamine Bis(Phenolato) Ligands: A New Class of Antitumor Agents

“…This behavior is in general different from that observed with titanocene dichloride and its analogues, in which replacement of two chloride ligands with a bidentate oxalate significantly enhanced activity. [48] What is the active species? As the active complexes [Ti(L n )-A C H T U N G T R E N N U N G (OiPr) 2 ] (n = 1, 2, and 4) showed indications for rather substantial formation of an O-bridged bis(phenolato) polynuclear species upon water addition, while the inactive complex 2 ] leads to complete bis(phenolato) ligand release, we were interested in exploring whether the polynuclear complexes might be the actual active species as suggested for budotitane derivatives, [18][19][20]49] despite the apparent formation of smaller amounts of a polynuclear cluster from 3 ], which is itself stable for days in the presence of water, was found to be inactive against the colon and ovarian cells measured ( Figure 17).…”

Cytotoxic Titanium(IV) Complexes: Renaissance

“…As complexes that hydrolyze rapidly are inactive, we conclude that a relatively inert tetradentate ligand is required to decelerate the hydrolysis of the labile groups upon formation of the inactive cluster for long enough periods to enable cell penetration and demonstration of cytotoxic activity. Nevertheless, some lability of the OR groups is required for allowing the fruitful biological interaction to occur, as replacing the isopropoxo groups with an inert catecholato ligand diminished the cytotoxic activity, contrary to the results obtained with oxalato titanocene Y (9, Scheme 3), [43] although other parameters may be engaged in the activity decrease that relate to the general different structure of the catecholato complex.…”

“…This result is different than that obtained for titanocene analogues, where substituting the chloro groups in titanocene Y (8) with a more inert oxalato ligand (9) (Scheme 3) enhanced the activity. [43] This implies that while the inertness of the tetradentate bis(phenolato) ligand is essential to stabilize an active Ti-based species and delay the hydrolysis of the X groups, the inertness of the additional X ligands should be more finely tuned. This observation is reminiscent of the one relating to titanocene dichloride (1), which exhibits enhanced cytotoxicity when is aged in certain organic co-solvents assumingly due to partial decomposition.…”

“…When tested against a panel of 36 human tumor-cell lines, the most promising candidate, titanocene Y (8) (Scheme 3), was found to have good activity against renal cell cancer. Interestingly, the oxalato complex 9 (Scheme 3), possessing a substantially less labile chelating ligand in replacement of the chloro groups, was reported to have a 13-fold increase in activity relative to 8 during in-vitro studies against the LLC-PK cell line, [43] yet in-vivo studies showed almost identical activity to 8. [44] Although the hydrolysis behavior of 8 and 9 was not studied in detail, it is possible that differences in the IC 50 values of 8 and 9 obtained invitro may in fact reflect the greater hydrolytic stability of 9.…”

Synthesis and cytotoxicity studies of novel anion‐exchanged Titanocene Y derivatives

“…Recently an oxalate derivative of Titanocene Y (Oxali-Titanocene Y) has been reported as having an IC50 of 1.6 µM on the LLC-PK cell line. [10] This was also shown to have good anti-angiogenic properties in a HUVEC anti-angiogenesis tests and in a mouse model was shown to be cytostatic on xenografted Caki-1. [11] Following the success of Titanocene Y and also Oxali-Titanocene Y in vivo and in vitro, which showed very promising cytotoxic, anti-angiogenic properties and probable different cytotoxic mechanism than cisplatin, it was necessary to make further carboxylate anionsubstituted derivatives of Titanocene Y and to do some preliminary in vitro biological testing.…”