Search

Despite the concerted efforts to develop targeted cancer treatments, these therapies are plagued by the rapid development of resistance and serious adverse drug reactions. Based on the wide clinical use and successes of the platinum drugs like cisplatin and oxaliplatin, we investigated the synthesis and potential anticancer efficacy of alternative platinum complexes. A series of nine cationic square planar platinum(ii) complexes were synthesized and characterized and then evaluated for their anticancer activity. The complexes were of the type [Pt(diimine)(Ln-κO,S)]+ where diimine is either 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp) or dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) and Ln-κO,S representing various N,N-dibutyl-N'-acylthiourea ligands. The anticancer activity of the synthesised complexes was evaluated against two lung cancer cell lines (A549 and H1975) and a colorectal cancer cell line, HT-29. The 50% inhibitory concentrations (IC50) for the most cytotoxic compounds were determined and the mode of cell death evaluated. The structure-activity relationships indicated that complexes with the 5,6-dimethyl-1,10-phenanthroline variation of the diimine ligand were the most active against the cell lines tested, while the activity of complexes based on the acylthiourea ligand varied between the cell lines. IC50 values for the three active platinum complexes were in the low micromolar range for the three cell lines and ranged between 0.68 μM and 2.28 μM. Changes to cell morphology indicate that the active platinum complexes induce cell death by both apoptosis and paraptosis. The complexes were able to induce the nuclear expression of the cyclin-dependent kinase inhibitor, p21, which is an indicator of DNA damage. The collective data indicate that these platinum complexes are valuable lead compounds for further analysis and cancer drug discovery.

Despite the availability of a myriad targeted treatments, resistance and treatment failures remains common in cancer treatment. Moreover, the high cost of targeted antibodies excludes a large cohort of patients from their benefits. In this context, copper-imidazo[1,2-a]pyridines were evaluated as alternative drug candidates against two common leukaemias, represented by HL-60 and K562 cells. A previous study identified JD88(21), JD47(29) and JD49(28) to be active against these cell lines with IC50 values between 1.9 and 6 μM and low leukocyte toxicity. To better understand their mechanism of action, their mode of cell death, effects on expression of apoptotic regulatory proteins and their respective genes were investigated. In both cell lines, the copper-imidazo[1,2-a]pyridines, at IC75 concentrations, caused membrane blebbing, raised phosphatidyl-serine levels on cell membranes and increased caspase-3 activity. A loss of mitochondrial membrane potential and activation of caspase-9, combined with poor caspase-8 activity indicated activation of intrinsic apoptosis. Apoptotic proteome analysis showed that the copper-imidazo[1,2-a] pyridines elevated protein levels of pro-apoptotic Bax and Smac/DIABLO in both cell lines, confirming their importance in apoptotic cell death. Conversely, though survivin was increased, this was counteracted by high levels of HTRA2/Omi expression. Effects on apoptotic regulatory proteins Bad, Bcl-2, XIAP and cIAP-1 was inconsistent between the copper-imidazo[1,2-a]pyridines and between the two cell lines, suggesting that the effect of the complexes was modulated by the molecular signature of each cell line. Analysis of mRNA transcripts showed a poor correlation between mRNA levels and associated proteins, implying that copper-imidazo[1,2-a]pyridines compromised protein synthesis and degradation.

The mixed-ligand [Pt(phen)(L1-κS)2] complex, in which two N,N-diethyl-N′-1-naphthoylthioureato ligands (L1)− coordinate in an unusual κS-thio/amido mode, crystallises in two solvatomorphs, form I and form II, whose structures have been determined by single crystal X-ray diffraction. These crystals were obtained from tetrahydrofuran and methanol/water respectively showing interesting sandwich (form I) and half-sandwich (form II) intramolecular π-stacking arrangements between the naphthoyl moiety of the acylthioureato ligands and the 1,10-phenanthroline ligand that adopt an anti-conformation above and below the square planar coordination plane. Variable temperature 1H and 195Pt NMR spectroscopy showed that these π-stacking arrangements persist in methanol solution especially at lower temperatures, where significant chemical shift shielding and asymmetry are observed indicating at least 3 conformers at −50 °C. A preliminary study indicates that this new compound may have potential as a new anticancer agent since it is active against the A549 lung cancer cell-line with an IC50 value of 6 ± 0.9 μM.

Metastatic colorectal cancer responds poorly to treatment and is a leading cause of cancer related deaths. Worldwide, chemotherapy of metastatic colorectal cancer remains plagued by poor efficacy, development of resistance and serious adverse effects. Copper-imidazo[1,2-a]pyridines were previously shown by our group to be selectively active against several cancer cell lines, with three complexes, JD46(27), JD47(29), and JD88(21), showing IC50 values between 0.8 and 1.8 μM against HT-29 cells. Here, we report that treatment with the copper complexes resulted in fragmented nuclei suggestive of apoptotic cell death, which was confirmed by increased annexin V binding and caspase-3/7 activity. The copper complexes caused a loss of mitochondrial membrane potential and increased caspase-9 activity. The absence of caspase-8 activity indicated activation of the intrinsic pathway. Proteomic analysis revealed that copper-imidazo[1,2-a]pyridines decreased the expression of phosphorylated forms of p53 [phospho-p53(S15), phospho-p53(S46) and phospho-p53(S392)]. The expression of inhibitor of apoptosis proteins, XIAP, cIAP1, livin, and the antiapoptotic proteins, Bcl-2 and Bcl-x, was decreased. HO/HMOX/HSP32, expression was notably increased, which suggested the accumulation of reactive oxygen species. Increased expression of TRAIL-R2/DR5 death receptor indicated the possible dual activation of both the extrinsic and intrinsic apoptotic pathways; however, caspase-8 activation could not be demonstrated. In conclusion, the copper-imidazo[1,2-a]pyridines were effective inducers of apoptotic cell death at low micromolar concentrations and changed the expression levels of proteins important for cell survival and cell death. These copper complexes may be useful tools to better understand the complexity of signalling networks in cancer cell death in response to cell stress.

Seventeen silyl- and trityl-modified (5′-O- and 3′,5′-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100 μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI50 values, with the best results being values of ∼25 μM.

1,2,3-Triazol-5-ylidene (trz) complexes of gold(i) containing a ferrocenyl substituent on the C4-position of the trz ring were synthesized to yield the neutral heterobimetallic gold(i) trz chlorido (2), gold(i) trz phenyl (3), and the cationic gold(i) trz triphenylphospine (5) complexes. In order to compare the effect of silver(i) as central metal vs. gold(i), [Ag(trz)2]+ (4) was also prepared, while variation of the C4-1,2,3-triazol-5-ylidene substituent from a ferrocenyl to a phenyl group was done to prepare the monometallic analogue of 5, namely the cationic Au(i) trz triphenylphosphine complex 6. The complexes were characterised with spectroscopic and electrochemical methods, and the single crystal X-ray structures of 2-6 were determined. NMR stability studies of 5 as a representative example of the series of complexes were performed to confirm the stability of the complexes in the solvent dimethylsulfoxide and in aqueous solution. The anti-cancer potential of 5 was evaluated against the lung cancer cell lines A549 and H1975, and the human embryonic kidney cell line (HEK-293) was used as a non-cancer model. IC50 values of 0.89, 0.23 and 5.43 μM, respectively, were obtained for A549, H1975 and HEK-293, respectively, indicating the activity and selectivity of 5 for cancer cells. Fluorescence microscopy experiments as a preliminary mode-of-action study evidenced an apoptotic cell death mechanism rather than necrotic cell death.

Iron deficiency, the most common cause of anaemia, is seemingly easy to manage. However, in many cases the nutritional deficiency is complicated by concurrent gastro-intestinal disease and/or inefficient absorption. In addition, iron absorption and mobilisation from physiological storage sites is regulated by the peptide hormone hepcidin, which is upregulated in anaemia associated with chronic inflammation. Successful patient management requires the continuous evaluation of iron status as well as monitoring of haemoglobin levels to measure treatment outcomes. Iron requirements change with patient physiological status and this must be taken into consideration when making clinical decisions. Provided that there is no underlying problem most patients respond rapidly to oral iron therapy. In non-responsive patients, and patients with concurrent gastro-intestinal disease, parenteral therapy must be considered. This brief review provides a summary of some of the problems that may be encountered with the management of iron deficiency and iron deficiency anaemia.

A small library of novel copper and zinc imidazo[1,2-a]pyridine complexes have been synthesized. Their structures were confirmed by X-ray diffraction crystallography and a selection of these compounds was tested against five cancer cell lines originating from breast cancer (MCF-7 and MDA-MB-231), leukemia (K562 and HL-60) and colorectal cancer (HT-29). The imidazo[1,2-a]pyridines and their zinc complexes showed poor anticancer activity, while the copper complexes were active against the cancer cell lines with IC50 values comparable to and lower than camptothecin. For example, copper 6-bromo-N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine acetate 21 had an IC50 value lower than 1 μM against the HT-29 cells. Fluorescence microscopy with acridine orange, Hoechst 33342 and ethidium bromide, used in a preliminary investigation to evaluate morphological changes showed that copper 6-bromo-N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine acetate 21 caused both apoptosis, necrosis and paraptosis in the MCF-7 and HL-60 cells. A select group of copper N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines (26, 27, 29 and 31) induced apoptosis, paraptosis and deformed nuclei in MCF-7 cells.

Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.