Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
| dc.contributor.author | Toh, Lee Roy | |
| dc.date.accessioned | 2022-06-23T00:31:43Z | |
| dc.date.available | 2022-06-23T00:31:43Z | |
| dc.date.issued | 2021-04 | |
| dc.description.abstract | Pharmacological inhibition of prolyl hydroxylase domain (PHD) enzymes have been suggested as an alternative method to upregulate hypoxia inducible factor (HIF) and serve as a therapeutic method for diseases such as anemia and cardiovascular disease. This study aims at evaluating five series of compounds: 2H-chromene-3-carboxylic acids (A1 – A3), triazine (B), pyrimidine (C), benzenesulfonamides (D1 – D4), and benzoxazolamine (E1 – E3) as PHD-2 inhibitors. The binding modes and free energies of A1 – E3 were first evaluated using molecular docking studies. The docking results demonstrated that all the tested compounds were capable of binding to the PHD-2 active site in a bidentate manner and forming salt bridge interaction with amino acid residue Arg383 apart from displaying preferential free energies of binding. The compounds were subsequently synthesized and characterized using FT-IR, HRMS, 1H NMR, 13C NMR and 2D NMR to confirm the structures. A1 – E3 were then screened for their inhibitory potencies against PHD-2 using a PHD-2 RapidFire assay. The inhibitory results revealed that compound E1 was a potent PHD-2 inhibitor, with IC50 value of 17.45 μM. On the other hand, ethyl ester E2 and E3 were synthesized and tested in cell-based study. However, they showed no ability to induce HIF-1α as an indicator of cellular PHD-2 inhibition. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/15444 | |
| dc.language.iso | en | en_US |
| dc.publisher | Universiti Sains Malaysia | en_US |
| dc.subject | Chemistry | en_US |
| dc.title | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors | en_US |
| dc.type | Thesis | en_US |
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