The Antiinflammatory Properties of Humic Substances: A Mini Review.

Humic substances are effective in the suppression of delayed type hypersensitivity, rat paw oedema, a graft-versus-host reaction and contact hypersensitivity in rats. They reduce the C-reactive protein levels of patients suffering from osteoarthritis of the knee and the wheel and flare reaction of patients suffering from hay fever. They have also been described as cardioprotective and pro-angiogenic. Toxicity studies have indicated that potassium humate is safe in humans up to a daily dosage of 1 g/kg, whereas fulvic acid is safe in humans up to a daily dosage of 1.8 g per adult. The antiinflammatory action of potassium humate can be contributed to the inhibition of the release of inflammatory-related cytokines, an adhesion molecule, oxidants and components of the complement system.

Superior cytotoxicity of hydrophylic gold carboxylato complexes over hydrophylic silver carboxylates.

BACKGROUND: The water-soluble ionic gold(I) complex [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl possesses at least ten times stronger antineoplastic activity than the water-soluble neutral silver(I) carboxylates [AgO(2)C(CH(2)OCH(2))(n)H], 1, (n=1), 2 (n=2), or 3 (n=3) even though Au(I) and Ag(I) are isoelectronic d(10) metals lying one above the other in the periodic table of the elements. In this study we determined the cytotoxicity of the stable water-soluble gold(I) carboxylates [(Ph(3)P)AuO(2)C(CH(2)OCH(2))(n)H], 4 (n=1), 5 (n=2) and 6 (n=3) to compare the intrinsic antineoplastic activity of gold(I) and silver(I) under conditions where different complex charges do not influence the result. MATERIALS AND METHODS: The cytotoxicity of carboxylato gold complexes 4-6 towards the HeLa (human cervix epithelioid) cancer cell line ATCC CCL-2, resting lymphocytes and phytohaemagglutinin(PHA)-stimulated lymphocytes were determined. Cell survival was measured by means of the colorimetric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. RESULTS: The IC(50) values of 4-6 from six experiments causing 50% cell growth inhibition were essentially constant; values ranged between 0.50 and 0.82 µmol dm(-3). Drug activity was thus independent of the carboxylato ligand chain length. Metal complexes 4-6 were at least one order of magnitude more cytotoxic towards the HeLa cancer cell line than the silver carboxylates 1-3 and were almost as cytotoxic as [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl and cisplatin [(H(3)N)(2)PtCl(2)]. Complexes 4-6 were also 2-5 times more toxic against PHA-stimulated lymphocyte cultures than to HeLa cancer cell. CONCLUSION: Unlike for the silver complexes 1-3, no meaningful drug activity-structural relationship exists for the gold(I) d(10) carboxylates 4-6. Gold(I) complexes in neutral and charged form are intrinsically more cytotoxic than silver(I) against the HeLa cancer cell line.

Cytotoxicity of ruthenocene-containing ß-diketones.

BACKGROUND: Ferrocene-containing ß-diketones and cisplatin, [(NH(3))(2)PtCl(2)], possess strong antineoplastic activity. No information is available regarding the anticancer activity of the corresponding ruthenocene complexes. This study examined the cytotoxicity of stable ruthenocene-containing ß-diketones. The results were related to the cytotoxicity of cisplatin and the ease of ruthenium electrochemical oxidation. MATERIALS AND METHODS: The ruthenocene-containing ß-diketones RcCOCH(2)COR where Rc=Ru(II)(C(5)H(5))(C(5)H(4)) and R=CF(3) (1), CH(3) (2), Ph=C(6)H(5) (3) and Fc=Fe(II)(C(5)H(5))(C(5)H(4)) (4) were tested for cytotoxicity against HeLa (human cervix epithelioid) cancer, COR L23 (human large cell lung carcinoma) and the platinum-resistant CoLo 320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colourimetric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. RESULTS: The 50% cell growth inhibition (IC(50)) values of 1-4 towards the cells ranged between 8.2 and 84.6 µmol dm(-3), with 1 being the most cytotoxic complex. Drug activity was directly proportional to the electron density on the ruthenium centre as well as the oxidation potential of the ruthenium core but inversely proportional to the pK(a) of the ß-diketones. The strongest activity was observed against the COR L23 cell line, and the weakest activity against COR L23 CPR. CONCLUSION: A drug activity-structural relationship exists for ruthenocene-containing ß-diketones in that drugs with the lowest electron density on the ruthenium centre are more cytotoxic. Compounds with larger ruthenium oxidation potentials and stronger acid strength (i.e. smaller pK(a) values) are more cytotoxic.

Cytotoxicity of hydrophylic silver carboxylato complexes.

BACKGROUND: Gold(I) and platinum(II) d(10) and d(8) electronic complexes such as (Au(PPh(2)CH(2)CH(2)PPh(2))(2))Cl and cisplatin, ((H(3)N)(2)PtCl(2)), possess strong antineoplastic activities. Almost no information is available regarding the anticancer activity of isoelectronic silver(I) d(10) complexes. This study examined the cytotoxicity of stable water-soluble silver(I) carboxylates. The results were related to the cytotoxicity of cisplatin and (Au(PPh(2)CH(2)CH(2)PPh(2))(2))Cl. MATERIALS AND METHODS: The silver carboxylates (AgO(2)CCH(2)OCH(3)), 1, (AgO(2)C-CH(2)OCH(2)CH(2)OCH(3)), 2, and (AgO(2)CCH(2)OCH(2)CH(2)OCH(2)CH(2)OCH(3)), 3, were investigated. Cytotoxicity tests were performed on the HeLa (human cervix epitheloid) cancer cell line, resting lymphocytes and PHA (phytohaemagglutinin)-stimulated lymphocyte cultures. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. RESULTS: The IC(50) (50% cell growth inhibition) values of 1-3 in the HeLa cells varied between 2.6 and 6.1 µmol dm(-3) with being 1 the most cytotoxic silver complex. Drug activity was inversely proportional to the length of the carboxylato chain length. Complexes 1-3 were 3-5 times more cytotoxic against the HeLa cancer cells than against the PHA stimulated lymphocyte cultures. CONCLUSION: A drug activity-structure relationship exists in that short-chain silver carboxylates are more cytotoxic than long-chain silver carboxylates, but silver d(10) complexes are one order of magnitude less cytotoxic than platinum(II) d(8) or gold(I) d(10) complexes.

Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on ß-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum.

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent ß-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials.

Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction.

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC(50) values of ≤10 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC(50) of 0.37 µM and the highest tumor specificity.

Cytotoxicity of ferrocenyl-ethynyl phosphine metal complexes of gold and platinum.

BACKGROUND: Ferrocene derivatives may possess antineoplastic activity. Those with low ferrocenyl reduction potentials often have the highest anticancer activity, as cell components have to oxidise them to the active ferrocenium species before cytotoxicity can be recorded. Some gold(I) complexes also possess anticancer activity. This study examined the cytotoxicity of ferrocenyl-ethynyl and ruthenocenyl-ethynyl complexes of gold and platinum. The results were related to the ease of iron oxidation in the ferrocenyl fragment and compared with the cytotoxicity of cisplatin, [(H(3)N)(2)PtCl(2)] and [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl. MATERIALS AND METHODS: Ferrocene-containing gold and platinum complexes of the type Fc-C≡C-PPh(2), 1, and Fc-C≡C-PPh(2)→M with Fc=ferrocenyl (Fe(II)(η(5)-C(5)H(5)) (η(5)-C(5)H(4))), Ph=phenyl (C(6)H(5)) and M=Au-Cl, 2, Au-C≡C-Fc, 3, or Au-C≡C-Rc, 4 (Rc=ruthenocenyl, (Ru(II)(η(5)-C(5)H(5)) (η(5)-C(5)H(4))) and the complex [(Fc-C≡C-PPh(2))(2)PtCl(2)], 5, were investigated. Cytotoxicity tests were determined on the HeLa (human cervix epitheloid) cancer cell line, ATCC CCL-2. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide assay. RESULTS: The IC(50) values of compounds 1-4 from four experiments causing 50% cell growth inhibition, ranged between 4.6 and 27 µmol dm(-3). Drug activity was inversely proportional to the sum of all formal reduction potentials, E(o'), of the ferrocenyl groups of the Fc-C≡C-PPh(2) and Fc-C≡C-ligands coordinated to the gold centre. The Fc-C≡C-PPh(2)→Au-Cl complex, compound 2, was most cytotoxic with IC(50)=4.6 µmol dm(-3) , demonstrating the beneficial effect the Cl(-) ion has on the cytotoxicity of these neutral gold complexes. The platinum complex [(Fc-C≡C-PPh(2))(2)PtCl(2)], compound 5, resembling the structure of cisplatin, in principle should exhibit good cytotoxicity, but was not tested due to its total insolubility in any biocompatible medium.

Cytotoxicity of a series of ferrocene-containing beta-diketones.

BACKGROUND: Oxidised ferrocenium compounds often possess antineoplastic activity. In contrast, reduced ferrocene derivatives frequently only show activity if cell components can oxidise them inside cells to the ferrocenium species. Ferrocene compounds having the lowest formal reduction potential are normally expected to be the most cytotoxic. Here we demonstrate this is not always the case. Some of the structure-related and physical properties that enhance ferrocenyl antineoplastic activity have been investigated. MATERIALS AND METHODS: Ferrocene-containing beta-diketones of the type FcCOCH2COR with Fc=ferrocenyl and R=CF3, CCl3, CH3, Ph(=C6H5, phenyl) and Fc, were tested for cytotoxicity against HeLa (human cervix epitheloid), COR L23 (human large cell lung carcinoma) and platinum resistant CoLo320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay. RESULTS: The mean drug concentration from 3 experiments causing 50% cell growth inhibition, (IC50) values, varied between 4.5 and 85.0 micromol dm(-3'), with the CF3(-) containing beta-diketone being the most active. Drug activity was inversely proportional to the formal reduction potential, Eo', of the ferrocenyl group, and dependent on the R group in the general beta-diketone structure. The CF3 complex was more cytotocic than cisplatin inter alia against platinum-resistant cell lines, and at least eight times more reactive against cancer cell lines than against PHA (phytohaemagglutinin)-stimulated lymphocyte cultures. CONCLUSION: A drug activity-structural relationship exists in that ferrocenyl drugs with halogen substituents chains are more cytotoxic. Compounds with higher ferrocenyl group formal reduction potential and stronger acid strength (i.e. smaller pKa value) are more cytotoxic.

Antineoplastic activity of a series of ferrocene-containing alcohols.

BACKGROUND: Often potentially good chemotherapeutic drugs find limited clinical use due to the many negative medical and physical side-effects they may exhibit. To combat these negative side-effects, new antineoplastic materials are continuously being synthesised and evaluated. Ferrocene-containing compounds under certain conditions may show appreciable anticancer activity. Some of the factors that determine this activity have been investigated. MATERIALS AND METHODS: Ferrocene-containing alcohols were tested for cytotoxicity against the HeLa cancer cell line. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide assay. RESULTS: The 50% lethal dosage of 4-ferrocenylbutanol was 5.72 micromol. dm(-3) and for 2-ferrocenylethanol and 3-ferrocenylpropanol it was 35.0 and 17 micromol. dm(-3) respectively while for ferrocenylmethanol IC50 was >100 micromol. dm(-3). CONCLUSION: A drug activity-structural relationship exists in that ferrocenyl drugs with longer side chains are more cytotoxic. Compounds with lower ferrocenyl group formal reduction potential are also more cytotoxic.

Synthesis of new 7-chloroquinolinyl thioureas and their biological investigation as potential antimalarial and anticancer agents.

New 7-chloroquinolinyl thiourea derivatives derived from the corresponding 4,7-dichloroquinoline isothiocyanate were synthesized and evaluated for in vitro antimalarial and anticancer activity. The most active compound from the series displayed an inhibitory IC(50) value of 1.2 microM against the D10 strain of Plasmodium falciparum. Lack of cytotoxicity towards HeLa cells indicates selectivity towards parasites.

Antibacterial activity of Venda medicinal plants.

Crude methanol and water extracts of 36 plants, employed in the treatment of diseases of probable bacterial etiology by the Venda people, were screened for antibacterial activity. Combretum molle, Peltophorum africanum, Piper capense, Terminalia sericea and Zanthoxylum davyi were the most active and presented MIC values < or =1.00 mg/ml.

Radiosensitization of CHO cells by two novel rhodium complexes under oxic and hypoxic conditions.

BACKGROUND: Tumour hypoxia severely limits the success of radiotherapy. Radiosensitization of hypoxic tumour cells by drugs is thus an important clinical issue. MATERIALS AND METHODS: Two novel ferrocene-containing beta-diketonato complexes of the transition metals rhodium and iridium were examined for their cytotoxic activity against Chinese hamster ovary (CHO) cells by MTT and clonogenic assays. The same complexes were also tested for their capacity to sensitize hypoxic CHO cells against 8 MeV photons. RESULTS: The IC50 for [Rh(fcta)(cod)] (I) and [Rh (fctca)(cod)] (II), where (fctfa) = ferrocenoylacetonato-4,4,4-trifluoro and (fctca) = ferrocenoyl-4,4,4-trichloro- and (cod) = 1,5-cyclooctadiene, were found to be 1.38 microM and 4.18 microM, respectively, closely resembling that of cisplatin which was found to be 1.21 microM. The rhodium (I) complex was identified as an effective anoxic radiosensitizer showing a dose-modifying factor (DMF) of 1.93 +/- 0.02, resembling cisplatin where the DMF was found to be 1.99 +/- 0.02. Small DMF's in the range of 1.10 were also found for cisplatin and the rhodium (I) complex under aerobic conditions, but these were not statistically significant. The DMF for the iridium complex was small and found to be 1.06 +/- 0.04. CONCLUSION: The cytotoxicity and radiosensitizing properties of the rhodium (I) complex are very similar to cisplatin and show considerable potential for clinical application.

Antimicrobial activities of seven novel tetramethylpiperidine-substituted phenazines against multiple-drug-resistant Gram-positive bacteria.

BACKGROUND: A dramatic increase in multiple-drug-resistant (MDR) Gram-positive pathogens has occurred in recent times, leading to increased rates or morbidity and mortality and also associated with high costs for the treatment of these infections. It is clear that there is an urgent need for the development of effective antimicrobial agents. The anti-bacterial activity of seven 2,2,6,6-tetramethylpiperidine (TMP)-substituted phenazines, compared to clofazimine (B663), were tested against 70 clinical isolates of methicillin-resistant Staphylococcus aureus, MDR Streptococcus pneumoniae and resistant Enterococcus sp. METHODS: Standard minimum inhibitory concentration agar dilution susceptibility tests were done on all isolates, including ATCC control strains. RESULTS: All the TMP-substituted phenazines were more active than clofazimine against all isolates tested. Compound B4125 was the most active by inhibiting all growth of the organisms tested, including vancomycin-resistant Enterococcus faecium. CONCLUSION: Clofazimine has been shown to have anti-staphylococcal activity. We demonstrate enhanced anti-bacterial activity of TMP-substituted phenazines against drug-resistant Gram-positive organisms compared to clofazimine.

Cytotoxicity of a series of water-soluble mixed valent diruthenium tetracarboxylates.

BACKGROUND: Mixed-valent diruthenium tetracarboxylate complexes were shown to have slight antineoplastic activity against P388 leukemia cell lines. However these complexes suffered from poor water-solubility, which may have detrimentally affected their activity. MATERIALS AND METHODS: Mixed-valent diruthenium tetracarboxylates of the type [Ru2(O2CR)4(L)2] (PF6) with L = imidazole, 1-methylimidazole and H2O when R = CH3, L = ethanol when R = Fc (ferrocenyl) or Fc-CH=CH- and of the type M3[Ru2(O2CR)4(H2O)2]4H2O, M = Na+ when R = m-C6H4SO3- and M = K+ when R = p-C6H4SO3-, were tested for cytotoxicity against HeLa and multidrug resistant CoLo 320DM human cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5dimethylthiazol-2-yl)-diphenyltetrazodium bromide assay. RESULTS: The mean drug concentration from 3 experiments causing 50% cell killing, ie, IC50 values, varied between 120 and 950 micromol dm(-3). CONCLUSION: The antineoplastic activity of the highly water-soluble m-sulpho derivative was the highest, while the poorly water-soluble imidazole derivatives did not exhibit any cytotoxic properties. The CoLo 320DM cancer cells were 5 times more prone to drug-induced cell death than the HeLa cells.