Cytotoxic activity of Gd(III)- and Dy(III)-complexes

The complexes of gadolinium(III) and dysprosium(III) were synthesized by reaction of the respective inorganic salts with 3,5-pyrazoledicarboxylic acid in amounts equal to metal to ligand molar ratio of 1 : 2. The structures of the final complexes were determined by means of spectral and elemental analyses. To help further the binding mode elucidation in the new Gd(III)- and Dy(III)-complexes of H(3)pdc, detailed vibrational analysis was performed on the basis of comparison of experimental vibrational spectra of the ligand and its Ln(III)-complexes using data theoretically predicted by us earlier, as well as data from the literature about related compounds. Significant differences in the IR and Raman spectra of the complexes were observed as compared to the spectra of the ligand. The ligand and the complexes were tested for their cytotoxic activities on the chronic myeloid leukemia-derived K-562, overexpressing the BCR-ABL fusion protein and the non-Hodgkin lymphoma-derived DOHH-2, characterized by a re-expression of the anti-apoptotic protein bcl-2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration-dependent manner, which enabled the construction of dose-response curves and the calculation of the corresponding IC(50) values. The inorganic salts exerted a very weak cytotoxic effect on these cells. This is in contrast to the lanthanide complexes, which exhibited potent cytotoxic activity, even more than the activity of cisplatin towards K-562 and DOHH-2 cell lines.     

New amides of 5-(4-chlorobenzoyl)aminoorotic acid: their synthesis and biological activity

The synthesis and in-vitro biological evaluation of the amide series 4 of 5-(4-chlorobenzoyl)aminoorotic acid 2 are presented. The biological properties of a few 5-(4-chlorobenzoyl)amino-2,6-dihydroxy-N-substituted-4-pyrimidinecarboxamide derivatives 4 tested here were compared with those of the isosteric isothiazole derivative MR-2/94 (5-(4-chlorobenzoyl)amino-N-(4-chlorophenyl)-3-methyl-4-isothiazolecarboxamide), which possesses a strong immunosuppressive and anti-inflammatory activity [1, 2], It must be suggested that replacement of the isothiazole by a pyrimidine core ring system resulted in considerable lowering of the anti-inflammatory and immunotropic actions of the obtained amides. Physicochemical properties of 2-(4-chlorophenyl)-6,8-dihydroxy-4H-pyrimido[5,4-d]-1,3-oxazin-4-on 3 are also briefly described.     

Synthesis,Cytotoxicity, and Apoptosis Induction Study of Antitumor Dinuclear Platinum(II) Complexes

Five novel dinuclear platinum(II) complexes with a new chiral ligand, 3‐(2‐amino‐cyclohexylamino)‐propionic acid (HP), were designed, prepared and spectrally characterized. The in vitro cytotoxicities of these compounds were evaluated against the HepG‐2, MCF‐7, A549, and HCT‐116 cell lines. The results indicated that all compounds showed cytotoxicity towards the HepG‐2 cell line. Particularly, complex X5 , which has SO as a bridge, exhibited better cytotoxicity than carboplatin or oxaliplatin against all selected cell lines. Moreover, double dyeing flow cytometric resection indicated that the target compounds inhibited tumor cell growth by inducing apoptosis.     

Synthesis of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone and their cytotoxic activity

A new series of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone were synthesized via four steps starting from 2-amino-5-methylbenzoic acid and initially screened against A-549 (human non-small cell lung cancer), HCT-8 (human colon cancer), and Bel-7402 (human liver cancer) cell lines at the single concentration of 5 microg/mL using the colorimetric MTT assay. The IC50 values were determined for the compounds reaching > or = 70% inhibition in primary screening by serial dilution. Among the newly synthesized compounds, 9n exhibited potent in vitro cytotoxicity against A-549, HCT-8, and Bel-7402 cell lines with the IC50 values of 1.65, 0.93, and 1.43 microM, respectively.     

Synthesis,characterization and cytotoxic activity of naturally isolated naringin-metal complexes

High-purity naringin was isolated from the fruit peels of Citrus maxima and characterized by various spectroscopic methods like UV and NMR. The isolated compound ligand (HL) was used as ligand-metal complexes synthesis after using Ag (I), Y (III) and Ru (III) metals. These ligand-metal complexes were characterized by elemental analysis, FT-IR, UV–VIS, TGA, molar conductance and magnetic properties. Cytotoxic activity of the isolated naringin and its metal complexes were investigated against two human cancer cell lines namely, white breast Adenocarcinoma (MCF7) and Lung carcinoma (A549) using cell viability assay. Transition metal increased the cytotoxic activity of naringin when they were conjugated. LC50 of Ag ligand complex demonstrated strong cytotoxicity against MCF-7 and A549 cell line that was found higher active more than three and four times the strength, respectively when compared to LC50 of Adriamycin. While LC50 of Adriamycin compound was slightly more active only about 30% and twice the strength of the Ru ligand complex against MCF-7 and A549 cell line, respectively.     

Chromium(III) complexes of D-glucosaminic acid and their effect on decreasing blood sugar in vivo

Two chromium(III) complexes of glucosaminic acid were synthesized by neutralization and exchange reaction. The formation of 1 : 1 and 2 : 3 (Cr : glucosaminate) complexes was confirmed by elemental analyses and spectroscopic studies. The effect of the complexes on decreasing blood sugar was investigated on type-2 diabetes model rats induced by tetraoxypyrimidine. The results indicated that the effect on decreasing blood sugar was comparable to that of picolinate chromium complex (Cr(pic)(3)) currently used world wide.     

Cytotoxic property of surfactant-cobalt(III) complexes on a human breast cancer cell line

The cancer chemotherapeutic potential of surfactant-cobalt(III) complexes, cis-[Co(bpy)(2)(C(14)H(29)NH(2))Cl](ClO(4))(2)·3 H(2)O (1) and cis-[Co(phen)(2)(C(14)H(29)NH(2))Cl](ClO(4))(2)·3 H(2)O (2) (bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline) on MCF-7 breast cancer cell was determined adopting MTT assay and specific staining techniques. The complexes affected the viability of the cells significantly and the cells succumbed to apoptosis as seen in the changes in the nuclear morphology and cytoplasmic features. Since the complex 2 appeared to be more potent, further assays were carried out on the complex 2. Single-cell electrophoresis indicated DNA damage. The translocation of phosphatidyl serine and loss of mitochondrial potential was revealed by annexin V-Cy3 staining and JC-1 staining respectively. Western blot analysis revealed up-regulation of pro-apoptotic p53 and down-regulation of anti-apoptotic Bcl-2 protein. Taken together, the surfactant-cobalt(III) complex 2 would be a potential candidate for further investigation for application as a chemotherapeutic for cancers in general and estrogen receptor-positive breast cancer in particular.     

Modulation of NAD(P)H:Quinone oxidoreductase (NQO1) activity mediated by 5-arylamino-2-methyl-4,7-dioxobenzothiazoles and their cytotoxic potential

Synthesized 5-arylamino-2-methyl-4,7-dioxobenzothiazoles 3a-3o were evaluated for modulation of NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 4,7-dioxobenzothiazoles affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 3a, 3b, 3g, 3h, 3n and 3o were considered as more potent cytotoxic agents, and comparable modulators of NQO1 activity.     

Synthesis and cytotoxic activity of 1-(1-benzoylindoline-5-sulfonyl)-4-phenylimidazolidinones

The novel 1-(1-benzoylindoline-5-sulfonyl)-4-phenyl-4,5-dihydroimidazolones 2 shows highly potent and broad cytotoxicities. Their cytotoxicities against human lung carcinoma A549, human chronic myelogenous leukemia K562, and human ovarian adenocarcinoma SK-OV-3 are compatible with doxorubicin. Compound 2p (1-[(4-aminobenzoyl)indoline-5-sulfonyl])-4-phenyl-4,5-dihydroimidazolone) exhibits a cytotoxicity that is far more potent than doxorubicin and also exhibits highly effective antitumour activities against murine (3LL, Colon 26) and human xenograft (NCI-H23, SW620) tumor models.     

Chromium(III) propionate complex supplementation improves carbohydrate metabolism in insulin-resistance rat model

The purpose of this study was to evaluate the antidiabetic potential and safety of the chromium(III) propionate complex (CrProp) in insulin resistance induced by a high-fructose diet in rats. The experiment was carried out on 32 nine-week old male Wistar rats divided into 4 groups of 8 rats each. Animals were fed at libitum: the control diet (AIN-93M), and high-fructose diets (HF) containing various levels of Cr(III) given as CrProp (1 mg Cr kg⁻¹ diet (HF) and supplemented with 10 mg Cr kg⁻¹ diet (HFCr10), or 50 mg Cr kg⁻¹ diet (HFCr50), equal to approx. 0.1, 1 and 5 mg kg⁻¹ body mass per day) for 8 weeks.     

Solid-phase synthesis of protected peptides using new cobalt(III) ammine linkers†

Cobalt(III) ammine complexes of the type cis-[CoL₄(4-AMB)O-AA-Boc](CF₃SO₃)₂, where L₄= bisethylenediamine (en)₂ or tetraammine (NH₃)₄, and 4-AMB = 4-(aminomethyl)benzoic acid, have been synthesized and used as linkers to polystyrene resins for solid-phase synthesis of protected peptides. Boc/t-Bu-protected [Leu⁵]enkephalin was assembled on the two different Co(III) resins, and then cleaved from the resins by reduction of the Co(III) center in 93–96%; yield. HPLC-purified protected [Leu⁵]enkephalin was obtained in 67–69% overall yield and characterized by amino acid analysis and ¹H NMR. Stepwise synthesis on the Co(en)₂-resin was also used in the assembly of Boc-Asp(OcHex)-Arg(Mts)-Gly-Asp(OcHex)-Ala-Pro-Lys(2Cl-Z)-Gly-OH, a sequence from collagen α1 Type 1. The protected peptide was cleaved from the Co(III) resin in 74% yield, and the HPLC-purified nonapeptide was characterized by amino acid analysis, ¹H NMR and liquid secondary-ion mass spectrometry (LSIMS). New routes are described for the synthesis of isomerically pure Co(III) anchor complexes. The Co(III) resins were found to be compatible with both the tert-butyloxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) N^α-protecting group strategies used in solid-phase peptide synthesis.     

Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24)

Aim of this study was to investigate the anticancer properties of the new lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24). In vitro, growth inhibition by KP772 was comparable for >60 tumour cell models with IC50 values generally in the low microM range. KP772 induced tumour cell apoptosis indicated by chromatin condensation, caspase substrate cleavage and mitochondrial membrane depolarisation. DNA is unlikely to represent the primary molecular target of KP772, as no significant interaction or damage of DNA was detectable both in vitro and in living cells. Moreover, we found no evidence for induction of radical species. In contrast, KP772 potently inhibited DNA synthesis paralleled by a massive block of cell cycle in G0/G1 phase and a selective decrease of cyclin B1. Although treatment with KP772 induced expression of p53 and p21Waf1, transfection of wild-type p53 into knock-out cells only marginally enhanced the cytostatic activity of KP772. In vivo, the anticancer activity of KP772 against human DLD-1 colon carcinoma xenografts was comparable to that of cisplatin and methotrexate at doses not causing significant adverse effects. With regard to toxicity, the LD50 and no-observed-adverse-effect levels (NOAEL) of KP772 in Sprague-Dawley rats were 21.6 and 7.5 mg/kg, in outbred albino mice 62 and 10 mg/kg, respectively. In summary, KP772 exerts anticancer activity via potent induction of cell cycle arrest and/or apoptosis and has promising in vivo anticancer activity against a human colon cancer xenograft. Together, these data suggest further development of KP772 as a new anticancer metal-drug.     

Evaluation of the acute oral toxicity class of tricentric chromium(III) propionate complex in rat

Chromium(III) is an essential element for carbohydrate and lipid metabolism, and various chemical forms of this element are widely used in dietary supplements. Of particular interest is [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺ cation (CrProp), that has been proposed as an alternative source of Cr. However, its safety has not been studied completely. In this study, we evaluated the acute toxicity class of CrProp in Wistar rats applying the OECD 423 procedure. Male and female Wistar rats (n = 12, 6 ♀ and 6 ♂) were given by gavage either a single dose of CrProp 2000 mg kg⁻¹ body mass or equivalent volumes of distilled water, and fed Labofeed B diet, and observed carefully for 14 days, than sacrificed to collect samples for biochemical and histologic examination. No death cases were detected, no major abnormalities in animal behaviour, body mass gains, gross organ histology, and blood morphology, and biochemistry were observed, except some changes of liver mass and the activity of ALT in female rats. The results demonstrate that LD₅₀ of CrProp is greater than 2000 mg kg⁻¹ when administrated orally to rat, thus this compound appears to be belong the fifth category in the GHS system or the fourth class (“unclassified”) in the EU classification system.     

The effects of tricentric chromium(III) propionate complex supplementation on pregnancy outcome and maternal and foetal mineral status in rat

Chromium(III) is an essential element for carbohydrate and lipid metabolism, and various chemical forms of this element are widely used as dietary supplements. Of particular interest is [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺ cation (CrProp), that has been proposed as an alternative source of Cr. However, its safety has not been studied completely. In this study we investigated the effects of CrProp supplementation on pregnancy outcome and maternal and foetal mineral status in the rat. Female Wistar rats (n = 20, 14 weeks old) were mated with males and, after successful conception were fed either AIN-93G diet supplemented with CrProp (100 mg Cr/kg diet, equals to 7.2 mg Cr/kg body mass/day) or non-supplemented diet (0.27 mg Cr/kg diet, equals to 0.02 mg Cr/kg body mass/day) for 21 days. Dams were sacrificed on 21 day of gestation, and their foetuses were examined for adverse effects. Maternal and foetal organs were analysed for minerals contents (Fe, Cu, Zn, Cr) using the AAS-method. Supplemental Cr given did not affect pregnancy outcome, litter size, body and inner organ masses, maternal blood biochemical indices. No abnormalities in gross organ morphology of foetuses were detected. Supplemental CrProp increased maternal liver and kidney Cr levels by 177% and 455%, decreased liver Cu and Zn concentrations by 9% and 12%, increased foetal liver Zn by 181%, and decreased kidney Cu level by 34%.     

Synthesis and antinociceptive activity of (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives

Ten new (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives have been synthesized. The compounds were tested for antinociceptive activity by tail clip, tail flick, hot plate and writhing test by using aspirin and dipyrone as standards. Among these compounds, 1-[3-(5-chloro-2(3H)-benzothiazolon-3-yl)-propanoyl]-4-(4-chlorophenyl)piperazine (11e) has been found to be significantly more active than the other compounds synthesized as well as the standards in all tests.     

Evaluation of anti-diabetic potential of chromium(III) propionate complex in high-fat diet fed and STZ injected rats

The aim of this study was to examine the anti-diabetic potential of the chromium(III) propionate complex (CrProp) in a diabetic rat model. Male Wistar rats (n = 28, 8-week old) were divided into 4 groups (with 7 rats each) and fed at libitum: the control diet (AIN-93M), and high-fat diets with or without supplementary CrProp (10 and 50 mg Cr kg⁻¹ diet; 1 and 5 mg kg⁻¹ body mass per day) for 5 weeks, and subsequently injected with STZ to induce diabetes. Rats were further fed the same diets for another week until the end of the experiment. Blood indices and the contents of minerals (Fe, Zn, Cu and Cr) in rat tissues were determined by atomic absorption spectrometry. Supplementary CrProp did not affect blood glucose level, but significantly improved insulin sensitivity (HOMA-IR index) and reduced serum levels of triacylglycerols, total and LDL cholesterols. Both supplementary dosages of CrProp (10 and 50 mg Cr kg⁻¹ diet) normalized the increased liver Fe content, reduced hepatic and renal Cu levels and elevated renal Cr contents in diabetic rats. In conclusion, CrProp has a significant anti-diabetic (insulin-sensitizing and hypolipidemic) potential; thus it might be a candidate for a therapeutic agent in diabetes.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

Genotoxicity assessment of chromium(III) propionate complex in the rat model using the comet assay

The aim of the study was to assess genotoxicity of a chromium(III) propionate complex in rat’s peripheral blood lymphocytes by the comet assay. The study was carried out on 18 12-weeks old female Wistar rats that were divided into three equal groups (six animals each): control (0), control-Cr(VI) and Cr(III)-tested rat fed ad libitum a basal diet and the diet supplemented either with 10 mg Cr(VI)/kg diet (given as K₂Cr₂O₇, equivalent of 1 mg/kg body mass/day) or 1000 mg Cr(III)/kg diet (given as [Cr₃O(O₂CCH₂CH₃)6(H₂O)₃]NO₃), equivalent of 100 mg Cr/kg body mass/day) for 4 weeks. High doses of supplementary Cr(III) were found to not affect body mass gain, feeding efficiency ratio and internal organ masses. Treatment of rats with the Cr(III) propionate complex, in contrast to Cr(VI), did not affect significantly the comet assay results in lymphocytes, which suggests that the compound does not exert genotoxic effects in rats.     

Synthesis, characterization and cytotoxicity of diam(m)-ineplatinum(II) complexes containing beta-phenylisosuccinate ligand

Four diam(m)ineplatinum(II) complexes containing beta-phenylisosuccinate as the leaving groups were prepared, characterized, and evaluated for their cytotoxicity against A549/ATCC human lung cancer cell line and SGC-7901 human gastric cancer cell line. One of the complexes, (trans-1R,2R-diaminocyclohexane)-beta-phenylisosuccinatoplatinum(II) 4, was much more active than cisplatin and carboplatin.