Searching for gallium bioactive compounds: Gallium(III) complexes of tridentate salicylaldehyde semicarbazone derivatives

In the search for gallium bioactive compounds five Ga(III) complexes, [GaIII(L–H)2](NO3), with tridentate salicylaldehyde semicarbazone derivatives as ligands (L) have been synthesized and characterized in the solid state and in solution by different techniques. The crystal structure of [GaIII(L4–H)2](NO3)·2H2O, where L4 is 3-ethoxysalicylaldehyde semicarbazone, was solved by X-ray diffraction methods. The gallium(III) ion is in a distorted octahedral environment, coordinated to two nearly planar and mutually perpendicular 3-ethoxysalicylaldehyde semicarbazonato anions acting as tridentate ligands through their phenol and carbonyl oxygen atoms and their azomethine nitrogen atom. Their biological potential has been explored by evaluating their activity on Mycobacterium tuberculosis, causative agent of tuberculosis, and their cytotoxicity on tumor cell lines. Three different human tumor cell lines were selected that show different degrees of resistance to metallodrugs: ovarian A2780 (low resistance), breast MCF7 (medium resistance) and prostate PC3 (high resistance) cells. Although the complexes have not shown activity on M. tuberculosis, complexation with gallium has led to the enhancement of the cytotoxic potencies of the organic compounds. Those complexes that contain a bromide substituent at the phenolate ring have shown the highest cytotoxicities. In particular, [GaIII(L2–H)2](NO3), where L2 is 5-bromosalicylaldehyde semicarbazone,·has shown a remarkable cytotoxicity on A2780 tumor cell line with an IC50 value of the same order than cisplatin (IC50 Ga–L2 = 2.4 ± 0.3 μM; IC50 cisplatin = 2.0 ± 0.1 μM, 72 h incubation at 37 °C). Interestingly, this complex has also shown moderate cytotoxicity against MCF7 and PC3 cells (IC50 MCF7 = 30 ± 6; IC50 PC3 = 18 ± 3 μM). Therefore, this gallium compound could be considered a promising wide spectrum potential anti-tumor agent.

Five [GaIII(L–H)2](NO3) complexes·of salicylaldehyde semicarbazone derivatives (L) were synthesized, characterized and evaluated on Mycobacterium tuberculosis and tumor cell lines showing different degrees of resistance to metallodrugs. The 5-bromosalicylaldehyde semicarbazone complex showed similar cytotoxicity than cisplatin on ovarian A2780 line and moderate cytotoxicity against breast MCF7 and prostate PC3 cells.Figure optionsDownload as PowerPoint slideHighlights
► New [Ga(L-H)2](NO3) complexes of salicylaldehyde semicarbazone derivatives were developed.
► The Ga(III) complexes did not show effects on Mycobacterium tuberculosis.
► Complexation with Ga enhanced the cytotoxic potency of the organic semicarbazone derivatives.
► Ga bromosalicylaldehyde semicarbazone complex resulted as cytotoxic as cisplatin on A2780 line.
► In addition, it showed cytotoxicity against breast MCF7 and prostate PC3 cells.