Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives

In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC₅₀: 0.49 ± 0.21 μM) and HCT15 (IC₅₀: 0.23 ± 0.02 μM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 μM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function.     

Transition metal complexes (M = Cu, Ni and Mn) of Schiff-base ligands: Syntheses, crystal structures, and inhibitory bioactivities against urease and xanthine oxidase

Six new transition metal complexes (M = Cu(II), Ni(II) and Mn(III)) of tridentate (H₂L¹, HL²) and/or bidentate (HL³, HL⁴) Schiff-base ligands, obtained from the condensation of salicylaldehyde with glycine, N-(2-aminoethyl)morpholine, 4-(2-aminoethyl)phenylic acid and 4-(2-aminoethyl)benzsulfamide, respectively, were synthesized and structurally determined by single-crystal X-ray analysis. Complexes 1-6 were evaluated for their effect on the jack bean urease and xanthine oxidase (XO). Copper(II) complexes 1-3 (IC₅₀ = 0.43-2.25 μM) showed potent inhibitory activity against jack bean urease, comparable with acetohydroxamicacid (IC₅₀ = 42.12 μM), which is a positive reference. And these copper(II) complexes (IC₅₀ = 10.26-15.82 μM) also exhibited strong ability to inhibit activity of XO, comparable to allopurinol (IC₅₀ = 10.37 μM), which was used as a positive reference. Nickel(II) and manganese(III) complexes 4-6 showed weak inhibitory activity to jack bean urease (IC₅₀ = 4.36-8.25 μM) and no ability to inhibit XO (IC₅₀ > 100 μM).     

Remarkable photocytotoxicity in hypoxic HeLa cells by a dipyridophenazine copper(II) Schiff base thiolate

Copper(II) complexes [Cu(satp)(L)] (1-3) of a Schiff base thiolate (salicylidene-2-aminothiophenol, H₂satp) and phenanthroline bases (L), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3), were prepared, characterized and their anaerobic DNA photocleavage activity and hypoxic photocytotoxicity studied. The redox active complexes show the Cu(II)-Cu(I) couple near − 0.5 V for 1 and near 0.0 V vs. SCE (saturated calomel electrode) for 2 and 3. The one-electron paramagnetic complexes (~ 1.85 μ_B) are avid DNA binders giving K_b values within 1.0 × 10⁵ − 8.0 × 10⁵ M^− 1. Thermal melting and viscosity data along with molecular docking calculations suggest DNA groove and/or partial intercalative binding of the complexes. The complexes show anaerobic DNA cleavage activity in red light under argon via type-I pathway, while DNA photocleavage in air proceeds via hydroxyl radical pathway. The DFT (density functional theory) calculations reveal a thyil radical pathway for the anaerobic DNA photocleavage activity and suggest the possibility of generation of a transient copper(I) species due to bond breakage between the copper and sulfur to generate the thyil radical. An oxidation of the copper(I) species is likely by oxygen in an aerobic medium or by the buffer medium in an anaerobic condition. Complex 3 exhibits significant photocytotoxicity in HeLa cells (IC₅₀ = 8.3(± 1.0) μM) in visible light, while showing lower dark toxicity (IC₅₀ = 17.2(± 1.0) μM). A significant reduction in the dark toxicity is observed under hypoxic cellular conditions (IC₅₀ = 30.0(± 1.0) μM in dark), while retaining its photocytotoxicity (IC₅₀ = 8.0(± 1.0) μM).     

Synthesis of rotenoid derivatives with cytotoxic and topoisomerase II inhibitory activities

6-Deoxyclitoriacetal (1) and a series of 11 further derivatives of it (2-12) were synthesized and evaluated for their cytotoxic and topoisomerase IIα inhibitory activities. Compounds bearing epoxide (2), morpholine (6) and benzylamine (10) moieties showed promising in vitro cytotoxic activities against four cancer cell lines, with IC₅₀ values ranging from 0.38 to 0.73 μM. These three compounds also strongly inhibited topoisomerase II activity at 68.3-93.5% and showed a moderately high DNA intercalating property.     

Synthesis and antitumor activity of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group

A series of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group were synthesized by successively nucleophilic substitutions of 5′-deoxy-5′-amino-ribonucleosides with 2,4-dichloropyrimidine and then with various fatty amines under microwave irradiation. Their anticancer activities in vitro were preliminarily evaluated. Compounds 7a and 8a only exhibited anticancer activity against A549 cell line with the IC₅₀ values of 10.73 and 10.99 μM, respectively. In addition, 7h and 8h showed potent activities against both A549 and Hela cell lines with the IC₅₀ values of 12.71, 8.55 and 8.44, 5.55 μM, respectively.     

Evaluation of in vitro cytotoxicity and hepatotoxicity of platinum(II) and palladium(II) oxalato complexes with adenine derivatives as carrier ligands

In vitro antitumour activity of the [Pt(ox)(L_n)₂] (1-7) and [Pd(ox)(L_n)₂] (8-14) oxalato (ox) complexes involving N6-benzyl-9-isopropyladenine-based N-donor carrier ligands (L_n) against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was studied. Some of the tested complexes were even several times more cytotoxic as compared with cisplatin employed as a positive control. The improved cytotoxic effect was demonstrated for the platinum(II) complexes 3 (IC₅₀ = 3.2 ± 1.0 μM and 3.2 ± 0.6 μM) and 5 (IC₅₀ = 4.0 ± 1.0 μM and 4.1 ± 1.4 μM) against A2780 and A2780cis, as compared with 11.5 ± 1.6 μM, and 30.3 ± 6.1 μM determined for cisplatin, respectively. The significant in vitro cytotoxicity against MCF7 (IC₅₀ = 8.2 ± 3.8 μM for 12) and A2780 (IC₅₀ = 5.4 ± 1.2 μM for 14) was evaluated for the palladium(II) oxalato complexes, which again exceeded cisplatin, whose IC₅₀ equalled 19.6 ± 4.3 μM against the MCF7 cells. Selected complexes were also screened for their in vitro cytotoxic effect in primary cultures of human hepatocytes and they were found to be non-hepatotoxic.     

Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules

From a library of compounds of natural sources, a big series of molecules was chosen by random sampling to evaluate their in vitro antimalarial activity against Plasmodium falciparum and their antifungal activity against Candida sp. From 184 molecules tested, no molecules were active against Candida sp. (MIC > 10 μg/ml) whereas 13 clearly showed high antiplasmodial activity in vitro, with an IC₅₀ less than 1 μg/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin (IC₅₀: 0.08 μg/ml), tchibangensin (IC₅₀: 0.13 μg/ml), ellipticin hydrochloride (IC₅₀: 0.17 μg/ml), usambarensin (IC₅₀: 0.23 μg/ml), 7S,3S-ochropposinine oxindole (IC₅₀: 0.25 μg/ml), 3,14-dihydro-ellipticin (IC₅₀: 0.25 μg/ml), tetrahydro-4′,5′,6′17-usambarensin 17S (IC₅₀: 0.26 μg/ml), ellipticine (IC₅₀: 0.28 μg/ml), aricin (IC₅₀: 0.3 μg/ml), 10-methoxy-ellipticin (IC₅₀: 0.32 μg/ml), aplysinopsin (IC₅₀: 0.43 μg/ml), descarbomethoxydihydrogambirtannin (IC₅₀: 0.46 μg/ml) and ochrolifuanin A (IC₅₀: 0.47 μg/ml). Among these 13 promising molecules, all except descarbomethoxydihydrogambirtannin, ochrolifuanine A and usambarensine presented here novel biological activities since they had never been described in the literature for their antiplasmodial activity. In spite of the large diversity of the molecules which have been tested, it is interesting to note that the ones active against Plasmodium are all indole derivatives (and one is both indolic and aminoimidazolic). To find new antiplasmodial compounds, ethnopharmacological approaches studying traditional medicine treatments for malaria is largely used but random research produced here an interesting yield (7%) of new antiplasmodial hits and appears therefore complementary to the traditional medicine way.     

Synthesis, characterization, X-ray structure and in vitro antimycobacterial and antitumoral activities of Ru(II) phosphine/diimine complexes containing the "SpymMe2" ligand, SpymMe2=4,6-dimethyl-2-mercaptopyrimidine

The reaction of cis-[RuCl₂(dppb)(N-N)], dppb = 1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe₂, 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe₂)(dppb)(N-N)]PF₆, N-N = bipy (1) and Me-bipy (2), bipy = 2,2′-bipyridine and Me-bipy = 4,4′-dimethyl-2,2′-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl₂(dppb)(N-N)], N-N = bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe₂. The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC₅₀ values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25 μg/mL, compared to the free ligands (MIC of 25 to >50 μg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC₅₀ values of 0.46 ± 0.02 and 0.43 ± 0.08 μM, respectively, against MDA-MB-231 breast tumor cells.     

Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS3

The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS₃)]²⁺ [(pp) = 2,2′-bipyridine (bpy), 2,2′-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), dipyrido[2,3-a:2′,3′-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl₃ · 3H₂O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2 [IC₅₀ values: 12.8 (±0.2) and 4.4 (±0.1) μM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC₅₀ values: 36.3 (±6.0) and 72.2 (±8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC₅₀ values of 72.2 (±8.0), 20.9 (±2.8) and 7.4 (±2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC₅₀ values: 1.7 (±0.5) and 1.9 (±0.1) μM] and tap (5) [IC₅₀ values: 11.5 (±0.6) and 7.6 (±4.8) μM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1 h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved.     

Vanadium polypyridyl compounds as potential antiparasitic and antitumoral agents: new achievements

In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [V^IVO(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC₅₀ values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC₅₀ 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC₅₀ 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC₅₀ 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC₅₀ values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells.     

Comparison of the SOD-like activity of hexacoordinate Mn(II), Fe(II) and Ni(II) complexes having isoindoline-based ligands

Recently, a series of Fe(II) complexes have been published by our group with 3 N-donor 1,3-bis(2′-Ar-imino)isoindoline ligands containing various Ar-groups (pyridyl, 4-methylpyridyl, thiazolyl, benzimidazolyl and N-methylbenzimidazolyl). The superoxide scavenging activity of the compounds showed correlation with the Fe(III)/Fe(II) redox potentials. Analogous, electroneutral chelate complexes with Mn(II) and Ni(II) in 2:1 ligand:metal composition are reported here. Each Mn(II) complex exhibits one reversible redox wave that is assigned as the Mn(III)/Mn(II) redox transition. The E_1/2 spans a 180 mV range from − 98 (Ar = 3-methylpyridyl) to 82 mV (Ar = thiazolyl) vs. the Fc⁺/Fc depending on the Ar-sidearm. The SOD-like (SOD=superoxide dismutase)activity of all complexes was determined according to the McCord-Fridovich method. The Mn(II) isoindolinates have IC₅₀ values - determined with 50 μM cytochrome c Fe(III) - that range from (3.22 ± 0.39) × 10^− 6 (Ar = benzimidazolyl) to (10.80 ± 0.54) × 10^− 6 M (Ar = N-methylbenzimidazolyl). In contrast with the Fe(II) complexes, the IC₅₀ concentrations show no significant dependence on the E_1/2 values in this narrow potential range emphasizing that the redox potential is not the governing factor in the Mn(II)-containing scavengers. The analogous Ni(II) compounds show no redox transitions in the thermodynamically relevant potential range (− 0.40 to 0.65 V vs. SCE) and accordingly, their superoxide scavenging activity (if any) is below the detection level.     

Identification of two antagonists of the scavenger receptor CD36 using a high-throughput screening model

CD36, a class B scavenger receptor, is an integral membrane protein that mediates the endocytosis of modified lipoproteins. The functions of CD36 are complex and have been associated with atherosclerosis. In the current study, we developed a high-throughput screening (HTS) assay to identify small molecule antagonists by expressing human CD36 using a Bac-to-Bac baculovirus expression system in Spodoptera frugiperda (Sf9) cells. Uptake of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-labeled acetylated low-density lipoprotein (DiI-AcLDL) revealed that the IC₅₀ values for the CD36 ligands oxidatively modified LDL (Ox-LDL), Ac-LDL, and high-density lipoprotein (HDL) were 0.039, 0.019, and 0.010 μg/ml, respectively. Using the HTS assay, two novel compounds, 2016481B and 2038751B, were found to inhibit DiI-AcLDL uptake in insect cells and exhibited IC₅₀ values of 17.4 and 23.7 μM, respectively. These two novel compounds also inhibited DiI-AcLDL uptake in cultured Chinese hamster ovary (CHO) cells permanently expressing human CD36. Furthermore, these two compounds inhibited lipid accumulation in RAW 264.7 murine macrophage cells in foam cell assays. This HTS assay represents a potential method for identifying more effective macrophage scavenger receptor antagonists, which may serve as starting points for the development of novel anti-atherosclerotic agents.     

Molecular docking,PASS analysis,bioactivity score prediction,synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes

2-Butanone thiosemicarbazone ligand was prepared by condensation reaction between thiosemicarbazide and butanone. The ligand was characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectrometry and UV spectroscopic studies. Docking studies were performed to study inhibitory action against topoisomerase II (Topo II) and ribonucleoside diphosphate reductase (RR) enzymes. Inhibition constants (K _i ) of the ligand were 437.87 and 327.4 μM for the two enzymes, respectively. The ligand was tested for its potential anticancer activity against two cancer cell lines MDA-MB-231 and A549 using MTT assay and was found to exhibit good activity at higher doses with an IC₅₀ = 80 μM against human breast cancer cell line MDA-MB-231. On the other hand, no significant activity was obtained against the lung carcinoma cell line A549. Antibacterial activity of the ligand was tested against Staphylococcus aureus and E. coli using the disc diffusion method. Ligand did not exhibit any significant antibacterial activity. Four complexes of Co(III), Fe(II), Cu(II), and Zn(II) were prepared with the ligand and characterized by various spectroscopic studies. Low molar conductance values were obtained for all complexes displaying non-electrolyte nature except in Co(III) complex. As expected, complexation with metal ions significantly increased the cytotoxicity of the ligand against the tested cell lines viz. IC₅₀ values of <20 μM for Co, Fe, and Zn complexes and approx. 80 μM against MDA cells versus IC₅₀ value of <20 μM for Co and Cu complexes and that of 30 and 50 μM for Fe and Zn complexes, respectively, against A549 cells. The Cu complex was found to be active against E. coli and S. aureus with MIC values in the range of 6–10 mg/mL. Other than Cu, only Co complex was found to possess antibacterial activity with MIC values of 5–10 mg/mL when tested against S. aureus. Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis also depicted the drug-like nature of ligand and complexes.     

Photocytotoxicity and near-IR light DNA cleavage activity of oxovanadium(IV) Schiff base complexes having phenanthroline bases

Oxovanadium(IV) complexes [VO(L)(B)] (1-3), where H₂L is a Schiff base ligand 2-(2-hydroxybenzylideneamino)phenol and B is 1,10-phenanthroline (phen for 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq for 2) or dipyrido[3,2-a:2′,3′-c]phenazine (dppz for 3), have been prepared, characterized and their DNA binding property and photo-induced DNA cleavage activity studied. Complex 3 which is structurally characterized by X-ray crystallography shows the presence of an oxovanadium(IV) moiety in a six coordinate VO₃N₃ coordination geometry. The complexes show a d-d band within 800-850 nm in DMF. The complexes display an oxidative response near 0.7 V versus SCE for V(V)-V(IV) and a reductive response within −1.1 to −1.3 V due to V(IV)-V(III) couple in DMF-0.1 M TBAP. The complexes are avid binders to calf thymus DNA giving binding constant values of 4.2 × 10⁴ to 1.2 × 10⁵ M⁻¹. The complexes do not show any “chemical nuclease” activity in dark. The dpq and dppz complexes are photocleavers of plasmid DNA in UV-A light of 365 nm via ¹O₂ pathway and in near-IR light (752.5 to 799.3 nm IR optics) by HO^• pathway. Complex 3 exhibits significant photocytotoxicity in visible light in HeLa cells giving IC₅₀ value of 13 μM, while it is less toxic in dark (IC₅₀ = 97 μM).     

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities

Complexes of the natural melophlins A and C with Mg, Zn, Ga, La and Ru were prepared, characterized and tested for antimicrobial and cytotoxic effects. The lanthanum complex La(melophlinato C)₃ and the ruthenium complex chlorido(η⁶-p-cymene)(melophlinato C)ruthenium(II) inhibited cells of human A-498 kidney cancer at IC₅₀ = 0.54 μM and 1.0 μM, respectively, and so distinctly better than free melophlin C. Another synergistic effect of coordinating melophlins to bioactive metals was found in the growth inhibition of the melophlin C-resistant bacterium Micrococcus luteus by Ga, La and Ru complexes of melophlin C.     

New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations: potential for incorporation into virostatic cocktails

Four bis(thiosemicarbazonate)gold(III) complexes (1-4) with a general formula [Au(L)]Cl {L = L1, glyoxal-bis(N⁴-methylthiosemicarbazone); L2, glyoxal-bis(N⁴-ethylthiosemicarbazone); L3, diacetyl-bis(N⁴-methylthiosemicarbazone); L4, diacetyl-bis(N⁴-ethylthiosemicarbazone)} were synthesised and screened for activity against the human immunodeficiency virus (HIV). Complexes 1-4 were characterised using ¹H-NMR and IR spectroscopy; and their purity established by micronanalysis. Complex 3 inhibited viral infection of TZM-bl cells by 98% (IC₅₀ = 6.8 ± 0.6 μM) at a non toxic concentration of 12.5 μM while complex 4 inhibited infection of these cells by 72 and 98% (IC₅₀ = 5.3 ± 0.4 μM) at concentrations of 6.25 and 12.5 μM respectively. The mechanism of inhibition of infection in TZM-bl cells is presumably as a result of the cytostatic or anti-proliferative activity that was observed for complex 4 in real time cell electronic sensing (RT-CES) and carboxyflourescein succinimidyl ester (CFSE) analysis. Treatment of T lymphocytes from HIV infected individuals with 4 decreased CD4+ T cell expression (p = 0.0049) as demonstrated by multi-parametric flow cytometry without suppressing cytokine production. None of the ligands (L1-L4) demonstrated anti-viral activity, supporting the importance of metal (gold) complexation in these potential drugs. Complexes 3 and 4 were shown to have ideal lipophilicity values that were similar when shake flask (0.97 ± 0.5 and 2.42 ± 0.6) and in silico prediction (0.8 and 1.5) methods were compared. The activity and drug-like properties of complexes 3 and 4 suggests that these novel metal-based compounds could be combined with virus inhibitory drugs to work as cytostatic agents in the emerging class of anti-HIV drugs known as virostatics.     

Oenothein B's contribution to the anti-inflammatory and antioxidant activity of Epilobium sp

Willow herb tea or preparation are available and relatively popular in the European market, and claimed to be effective inter alia because of their anti-inflammatory activity. The present study is therefore aimed at comparing the anti-inflammatory and antioxidant activity of extracts of the three most popular Epilobium species (E. angustifolium, E. hirsutum and E. parviflorum) and at juxtaposing this activity against the dominating compounds from the following extracts: oenothein B (OeB), quercetin-3-O-glucuronide and myricetin-3-O-rhamnoside. The phytochemical analysis of the extracts has shown that OeB quantities vary between 20% and 35%, while flavonoids content does not exceed 2%. All extracts have inhibited the activity of hyaluronidase and lipoxygenase with IC₅₀ around 5 μg/ml and 25 μg/ml. The inhibition of hyaluronidase is related with the presence of OeB, a strong inhibitor of this enzyme (IC₅₀ 1.1 μM). Additionally, the extracts inhibited myeloperoxidase (MPO) release from stimulated neutrophils. OeB inhibited MPO release similarly to the anti-inflammatory drug indomethacin with IC₅₀ 7.7 μM and 15.4 μM, respectively. Tested extracts significantly reduced the production of reactive oxygen species (ROS) from f-MLP and PMA induced neutrophils with IC₅₀ 5 μg/ml and 25 μg/ml, respectively. The flavonoids content seems to exert little influence on extracts’ activity, contrary to OeB, whose high concentration explains the activity of extract obtained from Epilobium. Tested currently marketed Epilobium preparations are often wrongly assigned, but we should stress that the level of OeB in all tested herbs was high and always exceeded 2% in raw material.     

Potent alpha-glucosidase inhibitors purified from the red alga Grateloupia elliptica

Diabetes mellitus is a most serious and chronic disease whose incidence rates are increasing with incidences of obesity and aging of the general population over the world. One therapeutic approach for decreasing postprandial hyperglycemia is to retard absorption of glucose by inhibition of α-glucosidase. Two bromophenols, 2,4,6-tribromophenol and 2,4-dibromophenol, were purified from the red alga Grateloupia elliptica. IC₅₀ values of 2,4,6-tribromophenol and 2,4-dibromophenol were 60.3 and 110.4 μM against Saccharomyces cerevisiae α-glucosidase, and 130.3 and 230.3 μM against Bacillus stearothermophilus α-glucosidase, respectively. In addition, both mildly inhibited rat-intestinal sucrase (IC₅₀ of 4.2 and 3.6 mM) and rat-intestinal maltase (IC₅₀ of 5.0 and 4.8 mM). Therefore, bromophenols of G. elliptica have potential as natural nutraceuticals to prevent diabetes mellitus because of their high α-glucosidase inhibitory activity.     

Appended 1,2-naphthoquinones as anticancer agents 1: synthesis, structural, spectral and antitumor activities of ortho-naphthaquinone thiosemicarbazone and its transition metal complexes

Copper(II), nickel(II), palladium(II) and platinum(II) complexes of ortho-naphthaquinone thiosemicarbazone were synthesized and characterized by spectroscopic studies. In both solution (NMR) and solid state (IR, single-crystal X-ray diffraction determination) the free ligand NQTS exists as the thione form. The Pd complex (X-ray) crystallizes as the H-bonded dimer, [Pd(NQTS)Cl]₂ · 2DMSO, where palladium(II) coordinates in a square planar configuration to the monodeprotonated, tridentate thiosemicarbazone ligand. The nickel(II) complex shows 1:2 metal to ligand stoichiometry while the other complexes exhibit 1:1 metal-ligand compositions. In vitro anticancer studies on MCF7 human breast cancer cells reveal that adding a thiosemicarbazone pharmacophore to the parent quinone carbonyl considerably enhances its antiproliferative activity. Among the metal complexes, the nickel compound exhibits the lowest IC₅₀ value (2.25 μM) suggesting a different mechanism of action involving inhibition of topoisomerase II activity.