Inhibition of lipoxygenase (LOX) and anticancer activity caused by gold(I) mixed ligands complexes of triphenylphosphine and thioamides.

Four mixed ligand gold(I) complexes with the thioamides 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) and triphenylphosphine (tpp) of formulae [Au(tpp)Cl] (1) [Au(tpp)(mtzd)] (2), [Au(tpp)(mbzt)] (3) and [Au(tpp)(Clmbzt)] (4), already known, were used to study their mechanism of inhibition activity towards the catalytic oxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX), kinetically and theoretically. The results are compared to those of cisplatin. In addition, the anticancer cell screening results against leimyosarcoma (LMS) cells have shown that 2-4 complexes were more active than cisplatin. The uptake of complexes in LMS cells were also studied with electrospray ionisation mass spectrometry spectroscopy.

Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides.

The reactions of tetrachloroauric(III) acid (HAuCl4) with the thioamides; 2-mercapto-benzothiazole (mbztH) and 5-ethoxy-2-mercapto-benzimidazole (EtmbzimH) lead to the desulfuration of the ligands and the formation of the ionic complexes {[AuCl4]- [bztH2]+} (1), and {[AuCl4]- [EtbzimH2]+ (H2O)} (2) (where bztH2+ and EtbzimH2+ are the desulfurated cations of the starting ligands). The reaction of HAuCl4 with 2-mercapto-nicotinic acid (mnaH2), however results in the formation of 2-sulfonate-nicotininc acid (C6H5NO5S) (3) with the simultaneous oxidation of the sulfur atom. On the other hand, the reactions of the gold(I) complex [Au(tpp)Cl] (4) (tpp = triphenylphosphine (Ph3P)) with the thioamides; 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) in the presence of potassium hydroxide resulted in the formation of the gold(I) complexes of formulae [Au(tpp)(mtzd)] (5), [Au(tpp)(mbzt)] (6) and [Au(tpp)(Clmbzt)] (7) without ligand desulfuration. All complexes have been characterized by elemental analysis, FT-IR, far-FT-IR,1H-NMR, spectroscopic techniques and X-Ray crystallography. The electrochemical behavior of 1, 2 and 4-7 complexes and the ligands EtmbzimH, mbztH and mnaH2 was also studied in acetonitrile and DMF using cyclic voltammetry. The results are in support of a mechanism of desulfuration of the ligands by Au(III), involving a first oxidation of S to -SO3-, followed by a C-S bond cleavage. This is also supported by PM6 calculations of bond dissociation energies of the various compounds involved. Complexes 1, 2 and 4-7 were tested for in vitro cytotoxicity against leiomyosarcoma cells and the results are discussed in relation with the geometry of the complexes and compared with those of cisplatin and other metals. Complexes 1 and 5 showed higher activity than that of cisplatin, while HAuCl4 was inactive against sarcoma cells.

Anticarcinogenic and antiplatelet effects of carvacrol.

AIM: To investigate the effect of carvacrol on chemical carcinogenesis, cancer cell proliferation and platelet aggregation, and to find possible correlation between all these processes and the antioxidant properties of carvacrol. MATERIALS AND METHODS: 3,4-benzopyrene-induced carcinogenesis model using Wistar rats was used. Leiomyosarcoma cells from Wistar rats were used to study carvacrol antiproliferative activity in vitro. The carvacrol antiplatelet properties were investigated with platelet aggregation assay and flow cytometry technique. The production of thromboxane B2, final metabolite of platelet aggregation, was evaluated by radioimmunoassay. RESULTS: Our study revealed significant anticarcinogenic properties of carvacrol. We observed 30% decrease of 3,4 benzopyrene carcinogenic activity in vivo. Antiproliferative activity of carvacrol (IC(50)) was 90 microM and 67 microM for 24 h and 48 h of incubation of cells, respectively. Carvacrol possessed also mild antiplatelet effect, inducing the decrease of thromboxane A2 production in platelets and as a result - restrictive expression of the GPIIb/IIIa platelet receptor. CONCLUSION: Our data demonstrated that carvacrol possesses anticarcinogenic, antiproliferative and antiplatelet properties.

The role of ascorbic acid, selenium, and glutathione on benzo[a]pyrene-induced carcinogenesis in wistar rats.

PURPOSE: The carcinogenic action of polycyclic aromatic hydrocarbons (PAHs) can be inhibited by endogenous or exogenous compounds. This study was designed to elucidate the modifying action of 3 endogenous inhibitors- ascorbic acid (vit C) used alone, and selenium (Se) used in combination with glutathione (GSH). MATERIALS AND METHODS: Chemical carcinogenesis was induced by benzo[a]pyrene(BaP). A hundred wistar rats were divided into 3 groups: the first group (G I) consisted of 42 animals, representing the control group. The two experimental groups (G II and G III) consisted of 38 and 20 rats, respectively. All groups were injected with BaP(10.08 mg subcutaneously-s.c). The first experimental G II was given only vit C (520 mg in 2% sugar solution per os - p.o.). The second experimental G III was given Se (0.1 mg p.o.) with GSH (200 mg p.o.). Tumor incidence and mean survival time were determined. Histological examination of the developed and excised tumors took place following death. The carcinogenic potency (CP) and anticarcinogenic potency (AP) of the substances used were calculated. RESULTS: A statistically significant difference regarding the mean survival time in the two experimental groups (238.4-/+31 days and 344.9-/+48 days, respectively) compared to the control group (183.8-/+28 days) was found (p < 0.001). The CP of each of the 3 groups was 54.3, 41.2, and 28.9 units, respectively. The AP of vit C used alone was 13.1 units, representing a significant anticarcinogenic effect. The combination of Se + GSH showed an AP of 25.4 units, resulting in a significant prolongation of the mean survival time, which is considered a potent anticarcinogenic effect. Furthermore, a statistically significant difference was found also when the mean survival time of G III animals was compared with G II. CONCLUSION: Vit C on its own and Se in combination with GSH represent strong endogenous inhibitors that can inhibit/reduce the carcinogenic action of BaP-induced carcinogenesis in wistar rats. The combination therapy used offered better in vivo results.