In vitro and in vivo antitumor properties of tetrakis((trishydroxy- methyl)phosphine)gold(I) chloride

A novel hydrophilic gold compound, tetrakis((trishydroxymethyl)phosphine)gold(I) chloride 1, has been investigated for its antitumor properties. In vitro studies demonstrate that 1 is active against HCT-15, AGS, PC-3, and LNCaP tumor cells. Cell cycle analysis of the HCT-15 cells by flow cytometry revealed elongation of the G1 phase of the cell cycle leading to growth inhibition. Administration of 1 to Balb/C mice inoculated with syngenic meth/A cells demonstrated statistically significant dose-dependent survival time.     

Inter-strand cross-links and single-strand breaks produced by gold(I) and gold(III) coordination complexes

The ability of gold coordination complexes to bind to DNA and produce inter-strand cross-links in DNA was assessed in an assay system based on the fluorescence properties of the DNA intercalative dye, ethidium bromide. Results from these studies using a variety of gold(I) and gold(III) complexes suggest that the ability of gold complexes to bind to and produce inter-strand cross-links in DNA is not dependent on the oxidation state of gold in the complex but is influenced by the nature of the coordinating ligands. Those complexes in which the gold was ligated through one or more weakly coordinating ligands showed evidence for DNA binding. However, only those complexes with two or more of these relatively weak coordinating ligands produced inter-strand cross-links. Both the amount of binding to and cross-linking of DNA by these compounds were decreased by treatment of the gold-DNA complex with 2-mercaptoethanol and other thiol containing agents. As shown by agarose gel electrophoresis, 2-mercaptoethanol caused a dissociation of the gold-DNA complexes and a regeneration of closed circular superhelical pBR322 DNA. DNA strand breakage also resulted from treatment of a number of gold-DNA complexes with 2-mercaptoethanol; this was observed with the gold compounds which were shown to produce inter-strand cross-links in DNA. The amount of DNA strand breakage produced by treatment of gold-DNA complexes with 2-mercaptoethanol was influenced by the initial conformation of the DNA; gold-DNA complexes which resulted from the binding of gold compounds to covalently closed superhelical DNA were more sensitive to the breakage induced by 2-mercaptoethanol treatment than those complexes in which closed circular, relaxed DNA was used as substrate. The DNA breakage was not reduced in partially anaerobic conditions or by free-radical scavengers, suggesting that it is not mediated by oxygen. The results are discussed with respect to the potential for the interaction of gold complexes with intracellular DNA and chromatin and their biological implications.     

Evaluation of in vitro antimicrobial and in vivo cytotoxic properties of some novel titanium-based coordination complexes

The aim of the present study was to determine the antimicrobial and cytotoxic activities of eight novel titanium(III) based coordination complexes [Ti(Pht)(2)(DL-serine)(2), S(1)], [Ti(Pht)(2)(glycine)(2), S(2))], [Ti(Pht)(2)(cystine)(2), S(3)], [Ti(Pht)(2)(DL-leucine)(2), S(4)], [Ti(Suc)(2)(L-leucine)(2), S(5)], [Ti(Suc)(2)(cystine)(2), S(6)], [Ti(Suc)(2)(cystein)(2), S(7)] and [Ti(Suc)(2)(DL-serine)(2), S(8)] against several gram-positive and -negative bacteria, fungi and brine shrimp nauplii. The investigation showed that almost all of the complexes were moderately active against tested bacteria and fungi at high concentration (200 microg/disc) compared with the standard antibiotic, amoxicillin and the antifungal agent, nystatin. In vivo lethality bioassay experiment showed that only S(7) and S(8) among the complexes had better cytotoxic effect than standard gallic acid. The LC(50) values of these two complexes were found to be 1.00 and 1.21 microg/ml, respectively. Thus the results suggest that only two complexes (S(7), S(8)) among the titanium(III) based coordination complexes show the anticancer properties comparable to the standard cytotoxic agent, and further studies of these two complexes may be helpful for their clinical implication.     

In vitro and in vivo antitumor activities and DNA binding mode of five coordinated cyclometalated organoplatinum(II) complexes containing biphosphine ligands

New complexes [Pt(C(∧)N)Cl(dppa)] (1), and [Pt(C(∧)N)Cl(dppm)] (2), (C(∧)N. deprotonated 2-phenylpyridine; dppa. bis(diphenylphosphino)amine; dppm. bis(diphenylphosphino)methane) were suggested to have pentacoordinated geometry as investigated by NMR and conductometry. Pharmacological effects of 1 and 2 were evaluated for their proteasome-inhibitory and apoptosis-inducing activities under in vitro and in vivo conditions, showing significant proteasome-inhibitory activity against purified 20S proteasome, while 2 demonstrated superior inhibitory activity against cellular 26S proteasome. Consistently, this effect was associated with higher levels of proteasome target proteins and apoptosis induction in breast cancer cells. Importantly, preliminary studies show 1 and 2 were able to exert a similar effect in vivo by inhibiting the growth of breast cancer xenografts in mice, which was associated with proteasome inhibition and apoptosis induction. Interaction of 1 and 2 with herring sperm DNA was investigated by fluorimeteric emission, suggesting that Pt(II)-containing biphosphine complexes with DNA binding capabilities can also target and inhibit the tumor proteasome.     

Gold(III) complexes as potential antitumor agents: solution chemistry and cytotoxic properties of some selected gold(III) compounds

Gold(III) complexes generally exhibit interesting cytotoxic and antitumor properties, but until now, their development has been heavily hampered by their poor stability under physiological conditions. To enhance the stability of the gold(III) center, we prepared a number of gold(III) complexes with multidentate ligands - namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2), and [Au(phen)Cl(2)]Cl - and analyzed their behavior in solution. The solution properties of these complexes were monitored by visible absorption spectroscopy, mass spectrometry, and chloride-selective potentiometric measurements; the electrochemical properties were also studied by cyclic voltammetry and coulometry. Since all the investigated compounds exhibited sufficient stability under physiological conditions, their cytotoxic properties were tested in vitro, via the sulforhodamine B assay, on the representative human ovarian tumor cell line A2780, either sensitive or resistant to cisplatin. In most cases the investigated compounds showed relevant cell-killing properties with IC(50) values falling in the 0.2-10 microM range; noticeably most investigated gold(III) complexes were able to overcome, to a large extent, resistance to cisplatin when tested on the corresponding cisplatin-resistant cell line. The cytotoxic properties of the free ligands were also determined under the same solution conditions. Ethylenediamine, diethylenetriamine, and cyclam were virtually nontoxic (IC(50) values > 100 microM) so that the relevant cytotoxic effects observed for [Au(en)(2)]Cl(3) and [Au(dien)Cl]Cl(2) could be quite unambiguously ascribed to the presence of the gold(III) center. In contrast the phenanthroline and terpyridine ligands turned out to be even more cytotoxic than the corresponding gold(III) complexes rendering the interpretation of the cytotoxicity profiles of the latter complexes less straightforward. The implications of the present findings for the development of novel gold(III) complexes as possible cytotoxic and antitumor drugs are discussed.     

Comparative in vitro evaluation of N-heterocyclic carbene gold(I) complexes of the benzimidazolylidene type

Gold(I) complexes with a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene (NHC) ligand of the type NHC-Au-L (L=-Cl, -NHC, or -PPh3) were comparatively evaluated as thioredoxin reductase (TrxR) inhibitors and antimitochondrial anticancer agents. Different effects were noted in various biochemical assays (e.g., inhibition of TrxR, cellular and mitochondrial uptake, or effects on mitochondrial membrane potential), and this was related to properties of the complexes such as bond dissociation energies and overall charge. Remarkable antiproliferative effects, a strong induction of apoptosis, and enhancement of reactive oxygen species (ROS) formation as well as other effects on tumor cell metabolism confirmed the promising potential of the complexes as novel anticancer chemotherapeutics.     

Antitumor activity of bis(diphenylphosphino)alkanes, their gold(I) coordination complexes, and related compounds

Bisphosphines related to bis(diphenylphosphino)ethane (dppe) and their gold complexes are described that are active in a spectrum of transplantable tumor models. When administered ip on days 1-5 at its maximally tolerated dose (MTD) of 40 mumol/kg, dppe reproducibly gives 100% increase in life span (ILS) in mice bearing ip P388 leukemia. Coordination of chlorogold(I) to each phosphine in dppe gave a complex that had similar activity but at a much lower dose level than dppe; the MTD for the gold(I) complex was 7 mumol/kg. Among other metal complexes of dppe, the Au(III) complex was active (greater than 50% ILS) whereas Ag(I), Ni(II), Pt(II), Pd(II), and Rh(I) complexes were inactive. Among dppe analogues, replacement of phenyl groups with ethyl or benzyl groups resulted in inactivity for both ligands and the corresponding gold complexes whereas substitution with cyclohexyl or heterocyclic ring systems yielded ligands and/or gold complexes with antitumor activity. Among substituted-phenyl dppe and dppe(AuCl)2 analogues, 3-fluoro, 4-fluoro, perdeuterio, 4-methylthio, and 2-methylthio analogues were active; 4-methyl, 3-methyl, 4-methoxy, 4-dimethylamino, and 4-trifluoromethyl analogues were marginal or inactive. Analogues in which the ethane bridge of dppe or dppe(AuCl)2 was varied between one and six carbons, unsaturated or substituted, revealed that activity was maximal with ethane or cis-ethylene. Compounds with good P388 activity were also active in other animal tumor models.     

Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.     

In vitro antitumor activity of the water soluble copper(I) complexes bearing the tris(hydroxymethyl)phosphine ligand

Monocationic hydrophilic complexes [Cu(thp)4](+) 3 and [Cu(bhpe)2](+) 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tumor cell lines. Complex 3 has been shown to be about 1 order of magnitude more cytotoxic than cisplatin. Chemosensitivity tests performed on cisplatin and multidrug resistance phenotypes suggested that complex 3 acts via a different mechanism of action than the reference drug. Different short-term proliferation assays suggested that lysosomal damage is an early cellular event associated with complex 3 cytotoxicity, probably mediated by an increased production of reactive oxygen species. Cytological stains and flow cytometric analyses indicated that the phosphine copper(I) complex is able to inhibit the growth of tumor cells via G2/M cell cycle arrest and paraptosis accompanied with the loss of mitochondrial transmembrane potential.     

Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates

We report the cytotoxicity toward B16 cells and antitumor activity in three transplantable tumor models of a series of ionic, tetrahedral, bischelated gold diphosphine complexes of the type [Au1(R2PYPR2')2]X, where Y = (CH2)2, (CH2)3, or cis-CH = CH. The anion (X = Cl, Br, I, CH3SO3, NO3, PF6) had little effect upon activity. The R = R' = phenyl complexes 1, 7, and 8 [Y = (CH2)2, (CH2)3, cis-CH = CH, X = Cl] were the most active against P388 leukemia, with an increase in lifespan ranging from 83 to 92% and were also active against M5076 sarcoma and B16 melanoma. Complexes with pyridyl or fluorophenyl substituents had reduced activities. For the latter, 19F and 31P NMR were used to verify the formation of bischelated gold(I) complexes in solution. The reduced activity of the complex with R = Et and R' = Ph and inactivity with R = R' = Et are discussed in terms of their increased reactivity as reducing agents. 31P NMR studies show that [AuI(Et2P(CH2)2PPh2)2]Cl readily reacts with serum, albumin, and Cu2+ ions to give oxidized ligand.     

糠酰异羟肟酸类有机锡配合物的合成及其抗癌活性

目的 设计合成糠酰异羟肟酸类有机锡配合物,并进行抗癌活性测定.方法 首先合成糠酰异羟肟酸(FuHA),并以之为配体合成一系列二烃基锡配合物;运用MTT法进行糠酰异羟肟酸类有机锡配合物对血癌K562细胞和骨髓瘤细胞EP-20的体外抗癌活性筛选.结果合成了1个配体和5个配合物,用熔点、元素分析、FT-IR、1H-NMR和13C-NMR等方法进行了结构表征,R2Sn(L)2型化合物为六配位畸变八面体,而[R2Sn(L)]2O型化合物为五配位双核三角双锥结构.结论正丁基锡和苯基锡配合物具有明显的抗癌活性.     

Correlation of in vitro activities of the fluoroquinolones to their in vivo efficacies

The new fluoroquinolones have activity against Gram-positive and Gram-negative bacteria. In order to differentiate between the compounds, the authors have compared their in vitro activities and correlated these results with their in vivo efficacies. Norfloxacin (N), pefloxacin (P), enoxacin (E), ofloxacin (O), difloxacin (D), ciprofloxacin (C), fleroxacin (F), A-61827 (A), temafloxacin (T) and lomefloxacin (L) were used in these studies. In vitro, C was the most active compound against Gram-negative aerobic bacteria and A was the most active compound against Gram-positive cocci and anaerobic bacteria. In mouse protection tests, C, D, A, O, T and F had similar activities against Escherichia coli and Pseudomonas aeruginosa. D, T and A were the most active quinolones against Staphylococcus aureus and Streptococcus pyogenes and Strep. pneumoniae in mouse protection tests. D was the most active agent against intracellular infection with Salmonella typhimurium, followed by O, T, A and F. The other compounds were ineffective in this test. All the quinolones were effective in treating E. coli pyelonephritis in mice. The doses required to treat P. aeruginosa pyelonephritis in mice were four times greater than those required to treat E. coli. Resistant P. aeruginosa mutants could be isolated from the kidneys after quinolone treatment. Systemic infections with E. coli, Staph. aureus and P. aeruginosa in neutropenic mice required high doses of the fluoroquinolones and F, T and A were ineffective at doses of 100 mg/kg against P. aeruginosa in this model. Differences in in vitro potencies were not reflected in in vivo efficacies.(ABSTRACT TRUNCATED AT 250 WORDS)     

卡培他滨类似物的合成及体内抗肿瘤活性

目的设计合成卡培他滨的类似物,并对其抗肿瘤活性进行评价.方法 以5′-DFUR为原料,经过羟基保护、胺化、酰化和脱保护等反应制得目标化合物;选择其中有代表性的3个化合物与卡培他滨对比,用人结肠癌裸小鼠移植瘤评价其抗肿瘤活性.结果与结论 共制得11个新化合物,经过1H-NMR、MS确证结构.抗肿瘤活性测试结果显示:N4-烷氧羰基中烷基的位阻和亲脂性对卡培他滨类似物的活性影响较大,且卡培他滨活性最好.     

Interactions of gold coordination complexes with DNA

The interactions of certain gold(I) and gold(III) complexes with isolated plasmid pBR322 DNA were defined and compared to those of cis-diamminedichloroplatinum(II), CDDP, using an agarose gel electrophoresis assay. Trichloro(pyridine)gold(III) appeared to bind to DNA as evidenced by its ability to produce dose-dependent changes in the electrophoretic mobilities of closed circular, supercoiled, closed circular, relaxed, and open circular plasmid DNAs. These effects suggest that the gold containing complex induces conformational changes in the plasmid as a result of the compound binding to the DNA and the subsequent unwinding of the double helix and shorting of the DNA. Auranofin [(2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S)-triethyl phosphine gold(I)] did not appear to interact with DNA under any conditions. However, its analog chloro(triethylphosphine) gold(I) interacted with DNA at pH 9.5 in borate buffer and produced electrophoretic mobility changes in pBR322 DNA which were different from those produced by the gold(III) complexes that were evaluated. Binding of chloro(triethylphosphine) gold(I) was inhibited by the co-addition of the thiosugar portion of auranofin suggesting preferential binding of the gold moiety to thiosugar, which results in the production of auranofin (or a sugar containing) gold complex and inhibition of gold binding to DNA. The interactions of a number of gold compounds with DNA were also evidenced by their abilities to inhibit the binding of ethidium bromide to DNA. The results from these studies indicate that: gold containing complexes can bind to, and produce conformational changes in, DNA; gold(I) and gold(III) complexes may interact with DNA via different chemical mechanisms to produce different conformational changes in DNA; and certain coordinating ligands in gold complexes (e.g. Cl, Br and SCN) can be exchanged for binding sites on DNA by gold.     

Anti-inflammatory active gold(I) complexes involving 6-substituted-purine derivatives

The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ mass spectrometry, conductivity, DFT calculations), and studied for their in vitro cytotoxicity and in vitro and in vivo anti-inflammatory effects on LPS-activated macrophages (derived from THP-1 cell line) and using the carrageenan-induced hind paw edema model on rats. The obtained results indicate that the representative complexes (1, 3, 6) exhibit a strong ability to reduce the production of pro-inflammatory cytokines TNF-α, IL-1β and HMGB1 without influence on the secretion of anti-inflammatory cytokine IL-1RA in the LPS-activated macrophages. The complexes also significantly influence the formation of edema, caused by the intraplantar application of polysaccharide λ-carrageenan to rats in vivo. All the tested complexes showed similar or better biological effects as compared with Auranofin, but contrary to Auranofin they were found to be less cytotoxic in vitro. The obtained results clearly indicate that the gold(I) complexes behave as very effective anti-inflammatory agents and could prove to be useful for the treatment of difficult to treat inflammatory diseases such as rheumatoid arthritis.     

甘草次酸-苦参碱复合物的合成及其抗肿瘤活性研究

目的：设计合成甘草次酸–苦参碱复合物,并对其体外抗肿瘤活性进行研究。方法以槐果碱、18α-甘草次酸和18β-甘草次酸为原料,经过加成、氧化、酯化缩合等反应合成目标化合物甘草次酸–苦参碱复合物,并采用MTT法对其进行体外抗肿瘤活性研究。结果设计并合成了目标产物甘草次酸–苦参碱复合物,利用MS和1H-NMR确证了结构;体外活性实验中,甘草次酸–苦参碱复合物的抗肿瘤活性明显高于甘草次酸及苦参碱,并优于对照药美法仑。结论甘草次酸–苦参碱复合物具有良好的抗肿瘤活性,尤其对肝癌细胞生长产生较好的抑制作用,值得进一步进行研究。     

Synthesis, spectroscopic characterization, X-ray structure, and in vitro antitumor activities of new triorganotin(IV) complexes with sulfur donor ligand

The discovery of the anticancer properties of cisplatin promoted a great deal of interest in the area of metal-based antitumor agents. With this aim, a new series of triorganotin(IV) derivatives: Ph₃SnL (1), BZ₃SnL (2), where L = morpholine-1-carbodithioate (MCDT) have been synthesized by the reaction of triorganotin(IV) chlorides with the ligand-salt in the appropriate molar ratio. All the complexes have been characterized by FT-IR, ¹H, ¹³C, and ¹⁹Sn NMR spectroscopy. In addition, the molecular structure of complex 1 was determined by single crystal X-ray diffraction study. X-ray crystallographic analysis shows that in the compound [Ph₃Sn(MCDT)], the Sn ion is in a four-coordinate environment with a dithiocarbamate ligand coordinated to the tin(IV) in a monodentate fashion through the sulfur atom. Furthermore, the cytotoxic activity of the free ligand (MCDT) as well as its triorganotin(IV) complexes were tested against tumor cell lines human cervix carcinoma HeLa, human myelogenous leukemia K562 and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. The cytotoxic results indicate that coupling of MCDT with R₃Sn(IV) metal center results in a complex with important biological properties and remarkable cytotoxic activity, since we observe IC₅₀ values better to that of the antitumor drug cisplatin.     

In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes

The antitumor activity of the organometallic ruthenium(II)-arene complexes, RuCl(2)(eta(6)-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)-arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma in the absence of a corresponding action at the site of primary tumor growth. Pharmacokinetic studies of RAPTA-C indicate that ruthenium is rapidly lost from the organs and the bloodstream.