| Summary: | <p>Well-regulated Ca<sup>2+</sup> signalling is essential for every living organism, and disruption of this signalling can lead to diseases including heart failure, neurological disorders and diabetes. Intracellular Ca<sup>2+</sup> levels are regulated by influx of extracellular Ca<sup>2+</sup> through channels located in the cell membrane. In addition, release of Ca<sup>2+</sup> from intracellular stores also plays an important role in controlling intracellular Ca<sup>2+</sup> concentration. Of the three types of intracellular Ca<sup>2+</sup> stores that have been characterised those with D-myo-Inositol 1,4,5 trisphosphate receptors (Ins<em>P<sub>3</sub> </em>Rs) showed a close relationship with cell proliferation. Hence, selective blockage of Ins<em>P<sub>3</sub> </em>Rs will allow better understanding of Ca<sup>2+</sup> signalling and might also unveil novel treatment for cancers, in the long term. There were no selective Ins<em>P<sub>3</sub> </em>Rs antagonists known at the start of these studies. Based on the crystal structure of Ins<em>P<sub>3</sub> </em>Rs bound to InsP3 and SAR studies of InsP3, we designed and tested several InsP3 analogues. Compound <strong>15</strong>, <strong>16</strong> and <strong>23</strong> acted as Ins<em>P<sub>3</sub> </em>R antagonists, though their selectivity for Ins<em>P<sub>3</sub> </em>Rs was not completely determined. Furthermore, we also attempted to improve the potency of <strong>16</strong> via substitution at the 1-postion phosphate. By considering the interaction formed between adenophosphostins and Ins<em>P<sub>3</sub> </em>Rs compounds (<strong>53-55</strong>) were designed and synthesised.</p> <p>In addition, analogues of compound <strong>92</strong>, selected from an in silico screen, have led to the discovery of another novel scaffold that acts as an Ins<em>P<sub>3</sub> </em>R antagonist.</p>
|
|---|