Vanadium Chloro-Substituted Schiff Base Catecholate Complexes are Reducible, Lipophilic, Water Stable, and Have Anticancer Activities

Abstract

A hydrophobic Schiff base catecholate vanadium complex was recently discovered to have anticancer properties superior to cisplatin and suited for intratumoral administration. This [VO(HSHED)(DTB)] complex, where HSHED is N-(salicylideneaminato)-N′-(2-hydroxyethyl)-1,2-ethanediamine and the non-innocent catecholato ligand is di-t-butylcatecholato (DTB), has higher stability compared to simpler catecholato complexes. Three new chloro-substituted Schiff base complexes of vanadium(V) with substituted catecholates as co-ligands were synthesized for comparison with their non-chlorinated Schiff base vanadium complexes, and their properties were characterized. Up to four geometric isomers for each complex were identified in organic solvents using 51 V and 1 H NMR spectroscopies. Spectroscopy was used to characterize the structure of the major isomer in solution and to demonstrate that the observed isomers are exchanged in solution. All three chloro-substituted Schiff base vanadium(V) complexes with substituted catecholates were also characterized by UV−vis spectroscopy, mass spectrometry, and electrochemistry. Upon testing in human glioblastoma multiforme (T98g) cells as an in vitro model of brain gliomas, the most sterically hindered, hydrophobic, and stable compound [t 1/2 (298 K) = 15 min in cell medium] was better than the two other complexes (IC 50 = 4.1 ± 0.5 μM DTB, 34 ± 7 μM 3-MeCat, and 19 ± 2 μM Cat). Furthermore, upon aging, the complexes formed less toxic decomposition products (IC 50 = 9 ± 1 μM DTB, 18 ± 3 μM 3-MeCat, and 8.1 ± 0.6 μM Cat). The vanadium complexes with the chloro-substituted Schiff base were more hydrophobic, more hydrolytically stable, more easily reduced compared to their corresponding parent counterparts, and the most sterically hindered complex of this series is only the second non-innocent vanadium Schiff base complex with a potent in vitro anticancer activity that is an order of magnitude more potent than cisplatin under the same conditions.

Vanadium(V) Pyridine‐Containing Schiff Base Catecholate Complexes are Lipophilic, Redox‐Active and Selectively Cytotoxic in Glioblastoma (T98G) Cells

“…Additionally, the HSHED Schiff base hydrolyzes into nontoxic decomposition products under physiological conditions. Another promising agent for intratumoral injections, [VO(Cl‐HSHED)(DTB)] (Cl‐HSHED= N ‐(5‐chlorosalicylideneaminato)‐ N’ ‐(2‐hydroxyethyl)ethane‐1,2‐diamine), has been reported recently [7c] . The addition of a chloro substituent on the Schiff base of parent complex increased hydrophobicity and tripled the half‐life for hydrolysis under physiological conditions, making the [VO(Cl‐HSHED)(DTB)] complex another promising agent for intratumoral injections [7c] …”

“…The [VO(HSHED)(DTB)] and [VO(Cl‐HSHED)(DTB)] complexes have complex dynamic isomer speciation with up to four geometric isomers in solution [7c] . This makes it difficult to determine which isomer(s) is/are responsible for the observed cytotoxicity and have the most influence on hydrolytic stability.…”

“…Little is known about the effects of the Schiff base structure and the substitution pattern on the catecholate ligand on the observed redox properties, and establishing those relationships is also of interest. The [VO(HSHED)L] and [VO(Cl‐HSHED)L] complexes show reversible couples in organic solvents [7c] . The stability of the reduced V IV species is attributed to the bulky hydrophobic substituents on the catecholate ligand and the stability of the five‐membered ring core between NN coordination sites of the Schiff base, the ethylene arm and V center [7c] .…”

Coordination-Driven Salamo-Salen-Salamo-Type Multinuclear Transition Metal(II) Complexes: Synthesis, Structure, Luminescence, Transformation of Configuration, and Nuclearity Induced by the Acetylacetone Anion

“…Coordination chemistry of studying the transition metal­(II/III) complexes of Schiff bases has been enhanced by the current advancements in the subjects of medicine and bioinorganic chemistry. , Schiff bases as the condensation result of an amine and a ketone or aldehyde with a general formula of R 2 CNR are well-known organic compounds. Up to now, a broad range of Schiff bases have been made and used as ligands to prepare coordination compounds. , Salamo-type ligands are developed from salen-type ligands, and oxygen atoms are added to the imines to enhance the stability of the ligand and prevent it from being hydrolyzed .…”

“…Fluorescence imaging images of zebrafish were collected using a TCS-SP8 laser confocal microscope. 1 H NMR and 13 C NMR spectra were obtained from an AMX500 spectrometer, reported in parts per million (δ, ppm) and referenced to residual protio-solvent (DMSO-d 6 , δ 2.5, 1 H; 39.5, 13 C) or tetramethylsilane (δ 0.00). Crystallographic Data Collection and Refinement.…”