The Therapeutic Potential of Gallium-Based Complexes in Anti-Tumor Drug Design

Abstract

The investigation of metal-containing drugs over several decades has set out to improve upon the toxicity and efficacy of conventional chemotherapeutic agents. Promising pre-clinical and clinical data have fostered the broadening for the search of metal compounds in cancer treatment and combination therapy. Gallium is only second to platinum in terms of anti-tumor activity. Its subsequent investigation has been ongoing for nearly three decades, primarily in the form of salts, and more recently coordinated to organic ligands as coordination complexes. From its early investigation as a diagnostic agent to its anti-tumor potential, promising clinical results have shown a renewed interest in exploring gallium in a host of malignancies, especially lymphoma and bladder cancer. However, the detailed mechanisms of action of gallium compounds are not completely defined. Further understanding the underlying mechanisms along with optimizing the structural components of gallium complexes will further improve the therapeutic index of gallium.

Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

“…Also, catalase activity was shown to be diminished, Fe metabolism being severely braked by Ga toxicity [47]. A series of [Ga(LX) 2 ]ClO 4 compounds ((LX) -= deprotonated form of ligands containing pyridine and 4,6-substituted phenol moieties with X = methoxy, nitro, chloro, bromo, and iodo) displayed growth-inhibition activity on cisplatin-resistant human neuroblastoma cells [48,49]. This class of compounds was also shown to target the proteasome [50].…”

Synthesis, characterization and cytotoxic activity of gallium(III) complexes anchored by tridentate pyrazole-based ligands

“…To overcome these limitations and seeking for compounds with more favorable pharmacokinetics, Ga(III) complexes anchored by multidentate chelators started to be evaluated in recent years as alternatives to gallium salts. In particular, the complexation of Ga(III) by multidentate chelators is expected to prevent hydrolysis processes, while improving bioavailability and cell membrane permeation of the compounds [1,2].…”

“…So far, the more promising results were reported for tris(-8-quinolinolato)gallium(III) (KP46) and tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III), two neutral complexes anchored by bidentate donors that are currently undergoing clinical evaluation [1,2]. Compared to gallium salts, several monocationic and homoleptic Ga(III) complexes anchored by tridentate chelators have also presented an enhanced cytotoxic activity against human tumor cells, namely cisplatin-resistant cell lines [3][4][5][6][7][8].…”

“…In this contribution, we report on the synthesis and characterization of cationic and homoleptic Ga(III) complexes (1)(2)(3)(4)(5)(6) anchored by (N, N 0 , O) pyrazolyl-containing chelators, as well as on the evaluation of their interest as cytotoxic metallopharmaceuticals. As shown in Fig.…”

Gallium(III) Ion Hydrolysis under Physiological Conditions

“…6 More recently, the use of complexes of Ga(III) with some ligands has emerged as a promising solution to create tumor inhibiting therapeutics. [7][8][9] In physiological conditions the behavior of the system Ga(III)-citrate has been subject to debate and there is no consensus regarding the composition and the structure of the species formed. 10 Numerous studies and particularly potentiometric titration and 71 Ga NMR experiments 11,12 have revealed that aluminium and gallium have a similar hydrolytic behavior.…”