Margo Nell

A cytotoxic bis(carbene)gold(I) complex of ferrocenyl complexes: Synthesis and structural characterisation

The N-heterocyclic carbene (NHC) precursors 1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)imidazolium bromide (2) and 1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)imidazolium tetrafluoroborate (3) were derived from 1-(4-ferrocenylphenyl)imidazole. Ferrocenyl complex 3 reacts with Ag2O and chloro(dimethylsulfide)gold(I) in the presence of tetraethylammonium chloride to produce the mixed metal species bis{1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)-2H-imidazol-2-ylidene}gold(I) tetrafluoroborate (4). Single crystal X-ray structure analyses of 1, 3 and 4 indicate that the NCHN-hydrogen in 3 is hydrogen bonded to the BF4− anion [C(H1)⋯F, 3.265(4) A], as is also reflected in the position of its 1H NMR chemical shift. Cytotoxicity studies show that complex 4 is selective for cancer cells and active against the tumour cell lines Jurkat and MCF 7.

Phosphinogold(I) dithiocarbamate complexes : effect of the nature of phosphine ligand on anticancer properties

The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1–3), [Au2L2(dppe)] (4–6), [(Au2L2)(dppp)] (7–9), and [Au2(L)2(dpph)] (10–12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4–6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1–3 and 7–12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 μM and 0.14 μM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers.

Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-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 β-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.

Novel N-heterocyclic ylideneamine gold(I) complexes : synthesis, characterisation and screening for antitumour and antimalarial activity

Ylideneamine functionalised heterocyclic ligands, 1,3-dimethyl-1,3-dihydro-benzimidazol-2-ylideneamine (I), 3-methyl-3H-benzothiazol-2-ylideneamine (II) or 3,4-dimethyl-3H-thiazol-2-ylideneamine (III), were employed in the preparation of a series of both charged and neutral gold(I) complexes consisting either of a Au(C(6)F(5)) fragment (1-3), a [Au(PPh(3))](+) unit (4-6) or a [Au(NHC)](+) unit (7) coordinated to the imine nitrogen of the neutral ylideneamine ligand. These complexes were fully characterised by various techniques including X-ray diffraction. In addition, the antitumour and antimalarial potential of selected compounds were assessed in a preliminary study aimed at determining the medicinal value of such compounds. Complexation of the azol-2-ylideneamine ligands with [Au(PPh(3))](+) increases their antitumour as well as antimalarial activity.

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.

The anti-tumour properties and biodistribution (as determined by the radiolabeled equivalent) of Au-compounds intended as potential chemotherapeutics

The anti-tumour activity of the Au (I) phosphine complex [Au(dppe(2)]Cl was first discovered in the mid 1980s although promising results were obtained it did not pass clinical studies because of its toxicity to organs such as the liver and heart. The aim of this study was to determine whether the two novel gold compounds (MM5 and MM6), selected for this study, have higher selectivity for cancer cells with less toxicity towards normal cells than [Au(dppe)(2)]Cl, and also to determine whether they have improved bio distribution compared to [Au(dppe)(2)]Cl. The Au-compounds as potential chemotherapeutic drugs were evaluated by using radioactive tracers in the in vitro and in vivo studies. Results obtained from these experiments showed that the uptake of these experimental compounds was dependent on their octanol/water partition coefficient. However; the inhibition of cell growth did not correlate with the uptake of these compounds by the cells that were tested. In terms of the total uptake it was found that the compounds that were less lipophilic (MM5, MM6) were taken up less efficiently in cells than those that are more lipophilic. Therefore hydrophilic drugs are expected to have a limited biodistribution compared to lipophilic drugs. This might imply a more selective tumour uptake.