A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G2/M phase further confirming their ability to inhibit tubulin polymerisation

Syntheses of Combretastatin A‐4 and Related Stilbenes by Using Aqueous Conditions

Combretastatin A-4 (CA4) is a potent anti-mitotic and vascular disrupting agent. Organic chemists have been working to optimize the synthesis of CA4 for the past 3 decades, with methods requiring hazardous solvents and harsh reaction conditions. Here, we report the synthesis of CA4 and a variety of stilbenes in an aqueous Wittig system. Potassium carbonate or lithium hydroxide were used as base in this Wittig reaction to give excellent yields of mixtures of E- and Z-stilbenes. The synthesis of CA4 was achieved using tetrahydropyran (THP) or silyl protected phenolic aldehydes. The THP groups were removed using dilute acid whilst the silyl groups fortuitously fell off during work up

Facile synthesis and biological evaluation of chrysin derivatives

In this paper, novel synthetic methods, including microwave O-alkylation, were used to produce several chrysin derivatives. These compounds were purified, characterised and tested on different cell lines and bacterial strains. From this family, 7-(2,4-dinitrophenoxy)-5-hydroxy-3-phenyl-4H-chromen-4-one (C3) was shown to be extremely active on bacterial strains methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae as well as having anticancer activity on a range of cancer cell lines with IC50 values less than 30 µM. Chrysin has been known for their anticancer and antimicrobial properties, and this study not only corroborates this but also shows that it is possible to synthesise new improved derivatives with therapeutic possibilities

Circular and linear : a tale of aptamer selection for the activation of SIRT1 to induce death in cancer cells

It is a challenge to select the right target to treat conditions without affecting non-diseased cells. Cancer belongs to the top 10 causes of death in the world and it remains difficult to treat. Amongst cancer emerging targets, silent information regulator 1 (SIRT1) – a histone deacetylase – has shown many roles in cancer, ageing and metabolism. Here we report novel SIRT1 ligands that bind and modulate the activity of SIRT1 within cells and enhance its enzymatic activity. We developed a modified aptamer capable of binding to and forming a complex with SIRT1. Our ligands are aptamers, they can be made of DNA or RNA oligonucleotides, their binding domain can recognise a target with very high affinity and specificity. We used the systematic evolution of ligands by exponential enrichment (SELEX) technique to develop circular and linear aptamers selectively binding to SIRT1. Cellular consequences of the interaction were monitored by fluorescence microscopy, cell viability assay, stability and enzymatic assays. Our results indicate that from our pool of aptamers, circular AC3 penetrates cancerous cells and is recruited to modulate the SIRT1 activity. This modulation of SIRT1 resulted in anticancer activity on different cancer cell lines. Furthermore, this modified aptamer showed no toxicity on one non-cancerous cell line and was stable in human plasma. We have demonstrated that aptamers are efficient tools for localisation of internal cell targets, and in this particular case, anticancer activity through modulation of SIRT1

Dibenzoyl-methane derivatives as potential and exciting new therapy for the treatment of childhood bone cancer

Abstract. Childhood bone cancer though rare, has very limited treatment choices, with poor survival rates and often involving amputation. We have developed a novel molecule, 2', 4'-dihydroxy-dithion-dibenzoyl-methane and tested it on hepatic, colon, lung and osteoblasts cancer cell lines. Thionylation of 2', 4'- dihydroxydibenzoylmethane led to selective targeting of bone cancer cells, stopping their growth and leading to their death without affecting non-cancerous cells within the bone marrow or other non-malignant cells

Use of competition dialysis in the discovery of G-quadruplex selective ligands

G-quadrplex DNA can exist in a rich variety of structural forms, ranging from unimolecular folded structures containing diverse types of loops and strand oreintations, to bimolecular dimeric structures, and finally to tetramolecular parallel-stranded structures. These diverse structures present numerous potential small molecule binding sites with distinctive properties. There is mounting evidence for important functional roles for G-quadruplex structures in biology. G-quadruplexes may participate in the maintenance of telomeres, in transcriptional regulation and, in mRNA, may act to modulate translation. G-quadruplexes thus represent an attractive target for new small-molecule therapeutic agents. Competition dialysis provides a useful tool for the discovery of small molecules that selectively recognize the unique structural features of G-quadruplexes. The principles and practice of the competition dialysis experiment are described here

Competition dialysis: a method for the study of structural selective nucleic acid binding

Competition dialysis is a powerful new tool for the discovery of ligands that bind to nucleic acids with structural- or sequence-selectivity. The method is based on firm thermodynamic principles and is simple to implement. In the competition dialysis experiment, an array of nucleic acid structures and sequences is dialyzed against a common test ligand solution. After equilibration, the amount of ligand bound to each structure or sequence is determined by absorbance or fluorescence measurements. Since all structures and sequences are in equilibrium with the same free ligand concentration, the amount bound is directly proportional to the ligand binding affinity. Competition dialysis thus provides a direct and quantitative measure of selectivity, and unambiguously identifies which of the samples within the array are preferred by a particular ligand. We describe here the third generation implementation of the method, in which competition dialysis was adapted for use in a 96-well plate format. In this format, we have been able to greatly expand the array of nucleic acid structures studied, and now can routinely study the interactions of a ligand of interest with 46 different structures and sequences

Circular dichroism to determine binding mode and affinity of ligand-DNA interactions

Circular dichroism (CD) is a useful technique for an assessment of DNA-binding mode, being a more accessible, low-resolution complement to NMR and X-ray diffraction methods. Ligand-DNA interactions can be studied by virtue of the interpretation of induced ligand CD signals resulting from the coupling of electric transition moments of the ligand and DNA bases within the asymmetric DNA environment. This protocol outlines methods to determine the binding mode and affinity of ligand-DNA interactions and takes approximately 7.5 h