Substitution Kinetics, Albumin and Transferrin Affinities, and Hypoxia All Affect the Biological Activities of Anticancer Vanadium(V) Complexes

Limited stability of most transition-metal complexes in biological media has hampered their medicinal applications but also created a potential for novel cancer treatments, such as intratumoral injections of cytotoxic but short-lived anticancer drugs. Two related V(V) complexes, [VO(Hshed)(dtb)] (1) and [VO(Hshed)(cat)] (2), where H₂shed = N-(salicylideneaminato)-N'-(2-hydroxyethyl)-1,2-ethanediamine, H₂dtb = 3,5-di-tert-butylcatechol, and H₂cat = 1,2-catechol, decomposed within minutes in cell culture medium at 310 K (t_1/2 = 43 and 9 s for 1 and 2, respectively). Despite this, both complexes showed high antiproliferative activities in triple-negative human breast cancer (MDA-MB-231) cells, but the mechanisms of their activities were radically different. Complex 1 formed noncovalent adducts with human serum albumin, rapidly entered cells via passive diffusion, and was nearly as active in a short-term treatment (IC₅₀ = 1.9 ± 0.2 μM at 30 min) compared with a long-term treatment (IC₅₀ = 1.3 ± 0.2 μM at 72 h). The activity of 1 decreased about 20-fold after its decomposition in cell culture medium for 30 min at 310 K. Complex 2 showed similar activities (IC₅₀ ≈ 12 μM at 72 h) in both fresh and decomposed solutions and was inactive in a short-term treatment. The activity of 2 was mainly due to the reactions among V(V) decomposition products, free catechol, and O₂ in cell culture medium. As a result, the activity of 1 was less sensitive than that of 2 to the effects of hypoxic conditions that are characteristic of solid tumors and to the presence of apo-transferrin that acts as a scavenger of V(V/IV) decomposition products in blood serum. In summary, complex 1, but not 2, is a suitable candidate for further development as an anticancer drug delivered via intratumoral injections. These results demonstrate the importance of fine-tuning the ligand properties for the optimization of biological activities of metal complexes.