Gallium(III) complexes with 2-acetylpyridine-derived thiosemicarbazones: antimicrobial and cytotoxic effects and investigation on the interactions with tubulin

Biometals. 2013 Feb;26(1):151-65. doi: 10.1007/s10534-012-9603-1. Epub 2013 Jan 24.

Abstract

Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Candida albicans / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Shape / drug effects
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Crystallography, X-Ray
  • Erythrocytes / drug effects
  • Gallium / chemistry*
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • MCF-7 Cells
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Protein Multimerization / drug effects
  • Pseudomonas aeruginosa / drug effects
  • Pyridines / chemistry
  • Staphylococcus aureus / drug effects
  • Thiosemicarbazones / chemistry*
  • Tubulin / chemistry*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology

Substances

  • Anti-Bacterial Agents
  • Antifungal Agents
  • Antineoplastic Agents
  • Coordination Complexes
  • Pyridines
  • Thiosemicarbazones
  • Tubulin
  • Tubulin Modulators
  • Gallium