Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
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 compo...
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| Format: | Thesis |
| Language: | English |
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2021
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| Online Access: | http://eprints.usm.my/53004/ http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf |
| _version_ | 1848882405078728704 |
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| author | Toh, Lee Roy |
| author_facet | Toh, Lee Roy |
| author_sort | Toh, Lee Roy |
| building | USM Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-15T18:34:23Z |
| format | Thesis |
| id | usm-53004 |
| institution | Universiti Sains Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T18:34:23Z |
| publishDate | 2021 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | usm-530042022-06-23T00:34:48Z http://eprints.usm.my/53004/ Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors Toh, Lee Roy QD1-999 Chemistry 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. 2021-03 Thesis NonPeerReviewed application/pdf en http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf Toh, Lee Roy (2021) Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors. Masters thesis, Perpustakaan Hamzah Sendut. |
| spellingShingle | QD1-999 Chemistry Toh, Lee Roy Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title_full | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title_fullStr | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title_full_unstemmed | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title_short | Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors |
| title_sort | synthesis and characterization of potential human hypoxia inducible factor (hif) prolyl hydroxylase domain 2 (phd-2) inhibitors |
| topic | QD1-999 Chemistry |
| url | http://eprints.usm.my/53004/ http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf |