A Short‐Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections

Abstract

The chemistry and short lifetimes of metal‐based anti‐cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1L2], where L1 is N‐(salicylideneaminato)‐N′‐(2‐hydroxyethyl)ethane‐1,2‐diamine and L2 is 3,5‐di‐tert‐butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8‐fold less toxic. 1 was 12‐fold more toxic than cisplatin in T98g cells and 6‐fold more toxic in T98g cells than in a non‐cancer human cell line, HFF‐1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal‐binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

Synthesis, Characterization, and In Vitro Insulin-Mimetic Activity Evaluation of Valine Schiff Base Coordination Compounds of Oxidovanadium(V)

“…Herein we evidenced for the first time that the newly developed vanadium-based compounds are stable in PBS for up to three hours, the stabil ity decreasing in time after that. The stability of some Schiff base vanadium(V) catecholate complexes in organic or aqueous solutions was found to be greater than in biological me dia (for example, culture cell media), without affecting the biological functions [8,9,37] These earlier observations may indicate that our four synthesized oxidovanadium(V compounds exhibit the same behavior in biological environments. However, the differen ways in which vanadium compounds are uptaken by cells (active or passive transport) [4 minimizes the disadvantage produced by the low stability of these compounds in biolog ical environments, without affecting the expected biological properties [8,9,37].…”

“…The stability of some Schiff base vanadium(V) catecholate complexes in organic or aqueous solutions was found to be greater than in biological me dia (for example, culture cell media), without affecting the biological functions [8,9,37] These earlier observations may indicate that our four synthesized oxidovanadium(V compounds exhibit the same behavior in biological environments. However, the differen ways in which vanadium compounds are uptaken by cells (active or passive transport) [4 minimizes the disadvantage produced by the low stability of these compounds in biolog ical environments, without affecting the expected biological properties [8,9,37]. Further For all complexes, decreases in the intensity for both depicted λ max were recorded, at 1 h (about 10% for 1a/1b, and less than 10% for 2a/2b, p < 0.05); 3 h (about 25% for 1a/1b, and less than 20% for 2a/2b, p < 0.01); 6 h (about 40% for 1a/1b, and 20% for 2a/2b, p < 0.01), 9 h (about 50% for 1a/1b and 30% for 2a/2b, p < 0.001); and 24 h (about 70% for 1a/1b and 30% for 2a/2b, p < 0.001) after solution preparation compared to initial recordings (T 0h) (Figure 5).…”

“…Herein we evidenced for the first time that the newly developed vanadium-based compounds are stable in PBS for up to three hours, the stability decreasing in time after that. The stability of some Schiff base vanadium(V) catecholate complexes in organic or aqueous solutions was found to be greater than in biological media (for example, culture cell media), without affecting the biological functions [ 8 , 9 , 37 ]. These earlier observations may indicate that our four synthesized oxidovanadium(V) compounds exhibit the same behavior in biological environments.…”

“…Therapeutic applications of vanadium and its compounds have been extensively studied since the 1990s [4]. Hence, a large number of in vitro and in vivo studies have demonstrated that vanadium salts and their well-known complexes have beneficial properties in diseases such as diabetes [4][5][6][7] and cancer [8,9]. Various complexes of oxidovanadium(IV/V) have been synthesized in the past three decades starting from the vanadyl ion and different ligands, such as amino acids, peptides, and Schiff bases, to improve compound stability, solubility, and bioavailability, properties mandatory for their biological effects [8,[10][11][12][13].…”

Open questions on the biological roles of first-row transition metals

“…Development of therapeutic and diagnostic agents continues because of the increasing need to monitor and cure diseases 16 . However, technical advances change the requirements for the agents, as illustrated by the recent report where the compound's reactivity was considered an advantage because injections were made directly into the tumor, and the reactivity of the compound affects cancerous tissue 17 . Multiple uses of the first-row transition metal ions in medicine are already in place in the clinic and other promising uses are being developed with the potential of improving human health.…”