A facile route for the preparation of 9-acridinecarboxamide derivatives
The synthesis of 9-acridinecarboxamide derivatides has been improved through the choice of better reaction conditions and the devising of an original treatment step. Extended amino chains are thus easily and reliably coupled to the commercially available
Identification of ligands for the Tau exona 10 splicing regulatory element RNA by using dynamic combinatorial chemistry
We describe the use of dynamic combinatorial chemistry (DCC) to identify ligands for the stem-loop structure located at the exona 10-5′-intron junction of Tau pre-mRNA, which is involved in the onset of several tauopathies including frontotemporal dementia with Parkinsonism linked to chromosomea 17 (FTDP-17). A series of ligands that combine the small aminoglycoside neamine and heteroaromatic moieties (azaquinolone and two acridines) have been identified by using DCC. These compounds effectively bind the stem-loop RNA target (the concentration required for 50% RNA response (EC50): 2-58μM), as determined by fluorescence titration experiments. Importantly, most of them are able to stabilize both the wild-type and the +3 and +14 mutated sequences associated with the development of FTDP-17 without producing a significant change in the overall structure of the RNA (as analyzed by circular dichroism (CD) spectroscopy), which is a key factor for recognition by the splicing regulatory machinery. A good correlation has been found between the affinity of the ligands for the target and their ability to stabilize the RNA secondary structure.