Described is the first modular construction of a G-quadruplex chiral catalyst. The key objective was to use G-quadruplex structures to act as chiral ligands that would allow access to either enantiomer of the product of a Diels-Alder reaction.
We report CD, ESI-MS and molecular modelling studies of ligand binding interactions with DNA quadruplex structures derived from the human telomeric repeat sequence (h-Tel) and the proto-oncogenic c-kit promoter sequence. These sequences form anti-parallel (both 2 + 2 and 3 + 1) and parallel conformations, respectively, and demonstrate distinctively different degrees of structural plasticity in binding ligands. With h-Tel, we show that an extended heteroaromatic 1,4-triazole (TRZ), designed to exploit pi-stacking interactions and groove-specific contacts, shows some selectivity for parallel folds, however, the polycyclic fluorinated acridinium cation (RHPS4), which is a similarly potent telomerase inhibitor, shows selectivity for anti-parallel conformations implicating favourable interactions with lateral and diagonal loops. In contrast, the unique c-kit parallel-stranded quadruplex shows none of the structural plasticity of h-Tel with either ligand. We show by quantitative ESI-MS analysis that both sequences are able to bind a ligand on either end of the quadruplex. In the case of h-Tel the two sites have similar affinities, however, in the case of the c-kit quadruplex the affinities of the two sites are different and ligand-dependent. We demonstrate that two different small molecule architectures result in significant differences in selectivity for parallel and anti-parallel quadruplex structures that may guide quadruplex targeted drug-design.
In this communication, we report the synthesis of ~5 mCi of [3-(14) C]solanesol (1) prepared from ethyl [3-(14) C]acetoacetate and (all-E)-octaprenyl bromide (2) in four steps, with a specific radioactivity of 19.83 mCi/mmol and with a chemical/stereochemical and radiochemical purity of ≥ 95%. (Figure ). Position 3 of the chain was selected for (14) C labelling because of the metabolic stability of this position. Unlabelled (all-E)-octaprenyl (18) (Scheme ) necessary for this work was prepared via a convergent iterative 'allyl-allyl' coupling approach of precursors easily derived from readily available inexpensive starting materials.(1)
Two-directional cross-metathesis of a range of alpha,omega dienes with a variety of electron deficient alkenes has been accomplished. It was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a very useful and high yielding protocol for two-directional chain elongation.
The synthesis and biological evaluation of a series of bifunctional acridine-HSP90 inhibitor ligands as telomerase inhibitors is herein described. Four hybrid acridine-HSP90 inhibitor conjugates were prepared using a click-chemistry approach, and subsequently shown to display comparable results to the established telomerase inhibitor BRACO-19 in the TRAP-LIG telomerase assay. The conjugates also demonstrated significant cyctotoxity against a number of cancer cell lines, in the sub-μM range.
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