Hydrolytically Stable and Cytotoxic [ONON]₂Ti(IV)-Type Octahedral Complexes

Abstract

A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized. X-ray structures of three derivatives revealed homoleptic L 2 Ti-type compounds that exhibit an octahedral geometry without binding of the dangling amine unit. DFT calculations demonstrated that the preference of an L 2 Ti complex is not driven by solvent or ligand substitutions but rather by entropic effects. Except for the fluorinated derivative that was hydrolyzed immediately following water addition at room temperature and had the lowest biological activity of the series tested, all other complexes showed cytotoxic activity comparable to or higher than (up to 10-fold) that of cisplatin toward human ovarian A2780 and colon HT-29 cancer cell lines (IC 50 values: 0.6−13 μM after incubation for 72 h). Activity was generally higher (up to 10-fold) toward the more sensitive ovarian line and similar for all active complexes, whereas differences were recorded toward the colon line that are attributed to bioavailability variations among the complexes analyzed. Particularly high hydrolytic stability was recorded for the brominated derivative with a t 1/2 of 17 ± 1 days for ligand hydrolysis in 10% D 2 O at room temperature, relative to t 1/2 of 56 ± 5 and 22 ± 6 h measured for the chlorinated and methylated derivatives, respectively. Altogether this series of compounds represent a promising family of anticancer agents, with the chlorinated derivative showing the best combination of stability, cytotoxicity, and bioavailability.

LVVO-Ethyl Maltol-Based Metallodrugs (L2– = Tridentate ONO Ligands): Hydrophobicity, Hydrolytic Stability, and Cytotoxicity via ROS-Mediated Apoptosis

“…Further, the hydrolytic stability of 1 – 4 was evaluated via time-dependent 1 H NMR spectroscopy by adding 10% D 2 O to the complexes in DMSO- d 6 . This study reflects probable knowledge about the relative stability of compounds in aqueous media with respect to time. , From the previous discussion, it was observed that 1 undergoes hydrolysis, whereas 2 – 4 remain stable under the investigation time period. Thus, considering the behavior of complexes, the 1 H NMR spectrum of 1 was collected every 15 min up to 17 h (Figure ), whereas for 2 – 4 , the spectra were collected every 1–2 h interval (Figure S18), and the peak intensity of selected signals was measured to get insights into the hydrolysis process of the complexes.…”

“…Finally, in nonhydrolyzed vanadium complexes ( 2 – 4 ), ethyl maltol played a major role in easing the transport and absorption in the lipid layer leading to enhancement in the cytotoxicity results. ,,, Thus, complex 2 with maximum hydrolytic stability and hydrophobicity values manifested as the most cytotoxic compound of the series. ,, However, 1 with poor hydrophobicity and hydrolytic stability, which was expected to show the least toxicity, is the second most toxic compound of the series, which may be due to the mixture of active species generated in the incubation media, i.e., the vanadium-hydroxyl, ethyl maltol, and traces of dimeric vanadium, along with the intact species. ,,,,, In addition, the results of biomolecular (CT–DNA/BSA) interaction studies of the complexes have correlated well with the cytotoxicity. − 1 and 2 with maximum DNA/BSA binding capacity exhibited maximum cytotoxicity, whereas 3 stands as an exception, though it has high log P ow and t 1/2 results, which showed poor biomolecular interaction resulting in potentially low cytotoxicity. Overall, from these detailed discussions, it can be stated that to be established as a better anticancer agent, a compound should have good hydrolytic stability, effective membrane internalization, and strong biomolecular interactions. ,,,,, …”

“…25,26,100 Again, the presence of the abovementioned electron-releasing bulky functional groups in 2−4 may also enhance the overall basicity of the ligands, which allows them to hold the metal ion strongly as compared to 1. 25,100 Further, the actual number of vanadium species that are formed upon hydrolysis is confirmed by 51 V NMR. As shown in Figure 3c, 51 V NMR of 1 (4:6 (v/v) D 2 O and DMSO-d 6 ) exhibits two peaks: one is at −456.66, which is due to [V V OL 1 (ema)] (solid-state structure), whereas the other peak is at −536.79 ppm probably due to the formation of [V V OL 1 (OH)] species.…”

“…49,51,116,117 Additionally, the major factors that enhanced the cytotoxicity of these vanadium complexes may be due to the combination of higher hydrophobicity and better hydrolytic stability, enabling better internalization of intact complexes in cells. 25,73,118,119 In this report, the obtained hydrophobicity results (log P ow ) are found to be 1.135 ± 0.07 for 1, 2.123 ± 0.01 for 2, 1.911 ± 0.01 for 3, and 1.391 ± 0.09 for 4 resulting in the order 1 < 4 < 3 < 2 (Table 5). It is important to mention that the free ligands (H 2 L 1−4 ) are found to be more hydrophobic than ethyl maltol (data not given); this suggests that 1−4 are probably hydrophobic because of the main ligands.…”

“…Recent research has suggested that [V IV (dtbc) 3 ] 2– (dtbc = 3,5-di- tert -butylcatecholato) exhibits anticancer activity through its hydrolysis/oxidation products, i.e., V IV O and V V O species . Also, various oxidovanadium species emerged as a potential anticancer agent for the treatment of “malignant melanoma” disease; to be precise, it has been shown that these compounds are found to be very effective toward the A-375 cancer cells. − Despite the vast exploration of these compounds as anticancer agents, they still have certain limitations such as rapid hydrolysis, poor hydrolytic stability, and cellular permeability that make them unsuitable for the design of standard metallodrugs for anticancer purposes. , Therefore, developing complexes that have improved hydrolytic stability and unique hydrolysis species is highly important for cytotoxicity studies. ,, Hence, designing the ligands with variations in the substituents in terms of the electronic and steric environment that can impact both the hydrolytic stability and cytotoxicity of the vanadium complexes would be the judicious selection. In this work, the hydrolytic stability of [V V OL 1–4 (ema)] ( 1 – 4 ) is strongly related to the cytotoxicity considering the pivotal role of ethyl maltol.…”