Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists
<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 influ...
| Yazar: | |
|---|---|
| Diğer Yazarlar: | |
| Materyal Türü: | Tez |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
2013
|
| Konular: |
| _version_ | 1826274871063085056 |
|---|---|
| author | Ye, Y |
| author2 | Conway, S |
| author_facet | Conway, S Ye, Y |
| author_sort | Ye, Y |
| collection | OXFORD |
| description | <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> |
| first_indexed | 2024-03-06T22:50:03Z |
| format | Thesis |
| id | oxford-uuid:5e75b5e0-d42a-4b58-9c46-7fabff99e10e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:50:03Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:5e75b5e0-d42a-4b58-9c46-7fabff99e10e2022-03-26T17:40:58ZDesign and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonistsThesishttp://purl.org/coar/resource_type/c_db06uuid:5e75b5e0-d42a-4b58-9c46-7fabff99e10eOrganic chemistryChemical biologyOrganic synthesisSynthetic organic chemistryLife SciencesPharmacologyEnglishOxford University Research Archive - Valet2013Ye, YConway, S<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> |
| spellingShingle | Organic chemistry Chemical biology Organic synthesis Synthetic organic chemistry Life Sciences Pharmacology Ye, Y Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title | Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title_full | Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title_fullStr | Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title_full_unstemmed | Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title_short | Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists |
| title_sort | design and synthesis of myo inositol 1 4 5 trisphosphate receptor antagonists |
| topic | Organic chemistry Chemical biology Organic synthesis Synthetic organic chemistry Life Sciences Pharmacology |
| work_keys_str_mv | AT yey designandsynthesisofmyoinositol145trisphosphatereceptorantagonists |