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
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id	my-usm-ep.53004
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spelling	my-usm-ep.530042022-06-23T00:34:48Z Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors 2021-03 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 http://eprints.usm.my/53004/ http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf application/pdf en public masters Perpustakaan Hamzah Sendut Pusat Pengajian Sains Kimia
institution	Universiti Sains Malaysia
collection	USM Institutional Repository
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
qualification_level	Master's degree
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
granting_institution	Perpustakaan Hamzah Sendut
granting_department	Pusat Pengajian Sains Kimia
publishDate	2021
url	http://eprints.usm.my/53004/1/TOH%20LEE%20ROY.pdf
_version_	1747822215532904448

Synthesis And Characterization Of Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors

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