Novel gold(I) complexes with 5-phenyl-1,3,4-oxadiazole-2-thione and phosphine as potential anticancer and antileishmanial agents.

The current anticancer and antileishmanial drug arsenal presents several limitations concerning their specificity, efficacy, costs and the emergence of drug-resistant cells lines, which encourages the urgent need to search for new alternatives. Inspired by the fact that gold(I)-based compounds are promising antitumoral and antileishmanial drug candidates, we synthesized novel gold(I) complexes containing phosphine and 5-phenyl-1,3,4-oxadiazole-2-thione and evaluated their anticancer and antileishmanial activities. Synthesis was performed by reacting 5-phenyl-1,3,4-oxadiazole-2-thione derivatives with chloro(triphenylphosphine)gold(I) and chloro(triethylphosphine)gold(I). The novel compounds were characterized by infrared, Raman, 1H, 13C nuclear magnetic resonance, high-resolution mass spectra, and x-ray crystallography. The coordination of the ligands to gold(I) occurred through the exocyclic sulfur atom. All gold(I) complexes were active at low micromolar or nanomolar range with IC50 values ranging from <0.10 to 1.66 µM against cancer cell lines and from 0.9 to 4.2 µM for Leishmania infantum intracellular amastigotes. Compound (6-A) was very selective against murine melanoma B16F10, colon cancer CT26.WT cell lines and L. infantum intracellular amastigotes. Compound (7-B) presented the highest anticancer activity against both cancer cell lines while the promising antileishmanial lead was compound (6-A). Tiethylphosphine gold(I) complexes were more active than the conterparts triphenylphosphine derivatives for both anticancer and antileishmanial activities. Triethylphosphine gold(I) derivatives presented antimony cross-resistance in L. guyanensis demonstrating their potential to be used as chemical tools to better understand mechanisms of drug resistance and action. These findings revealed the anticancer and antileishmanial potential of gold(I) oxadiazole phosphine derivatives.

Improved pharmacological profile of the lipophilic antitumor dichloro-(N-dodecyl)-propanediamine-platinum(II) complex after incorporation into pegylated liposomes.

Liposome encapsulation of platinum (Pt) drugs has emerged as a promising strategy to overcome their toxicity and cellular Pt resistance. The aim of the present work was to examine the impact of liposome encapsulation of a novel antitumor lipophilic Pt complex, dichloro-(N-dodecyl)-propanediamine-platinum(II) complex (DDPP), on its pharmacological profile as an antitumor agent. Biological assays included acute toxicity and histopathological evaluations, pharmacokinetics, and growth inhibition of B16-F1 tumor cells in C57Bl/6 mice. Comparison was made with cisplatin and free DDPP dissolved in castor oil. DDPP encapsulated in pegylated liposomes showed reduced acute toxicity in mice following intraperitoneal administration, compared with the free complex. Free DDPP at 5 mg Pt/kg induced histopathological alterations in the liver, in contrast to liposomal DDPP and cisplatin. Interestingly, the marked loss of body weight following the treatment of mice with cisplatin was not observed after liposomal DDPP at the same Pt dose. Liposomal DDPP was found to inhibit tumor growth significantly, when administered at 5 mg Pt/kg/day for 3 days, similar to cisplatin, but in contrast to the free complex. Pharmacokinetic studies after intraperitoneal and intravenous administrations at 5 mg Pt/kg indicated greater and more prolonged Pt levels in the plasma, liver, spleen, and kidneys from liposomal DDPP, compared with free DDPP or cisplatin. The tumor concentration of Pt increased after liposomal DDPP over the 24-h period, whereas it decreased after cisplatin. In conclusion, the encapsulation of DDPP in pegylated liposomes reduced the drug toxicity and enhanced its antitumoral activity in mice, as a result of improved drug pharmacokinetics.

Synthesis and antitubercular activity of palladium and platinum complexes with fluoroquinolones.

The fluoroquinolones are an important family of synthetic antimicrobial agents being clinically used over the past thirty years. In addition, some fluoroquinolones have been used in the development of anticancer drugs, and others have demonstrated anti-HIV activity. Furthermore, there has been some additional work investigating the effect of metal ions on biological activity. Aiming to obtain novel palladium(II) and platinum(II) complexes that exhibit biological activity, we have synthesized complexes using fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin, and gatifloxacin) as ligands. The compounds were characterized using IR and NMR spectroscopy, thermogravimetric and elemental analyses. The complexes show activity against Mycobacterium tuberculosis strain H(37)Rv. The minimal inhibitory concentration (MIC) of the complexes was determined.