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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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Main Author: Toh, Lee Roy
Format: Thesis
Language:English
Published: 2021
Subjects:
QD1-999 Chemistry
Online Access:http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf
http://eprints.usm.my/53004/
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spelling my.usm.eprints.53004 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.
institution Universiti Sains Malaysia
building Hamzah Sendut Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Sains Malaysia
content_source USM Institutional Repository
url_provider http://eprints.usm.my/
language English
topic QD1-999 Chemistry
spellingShingle QD1-999 Chemistry
Toh, Lee Roy
Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
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.
format Thesis
author Toh, Lee Roy
author_facet Toh, Lee Roy
author_sort Toh, Lee Roy
title 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_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_sort synthesis and characterization of potential human hypoxia inducible factor (hif) prolyl hydroxylase domain 2 (phd-2) inhibitors
publishDate 2021
url http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf
http://eprints.usm.my/53004/
_version_ 1736834789062737920
score 13.211869

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