Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors

There is a widespread interest in developing the human hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors for the treatment of ischemic/hypoxic diseases. In this study, a new series of 4-oxobutanoic acid analogues was investigated as potential HIF prolyl hydroxylase domain-2 (PHD-2) inhibi...

Full description

Saved in:

Bibliographic Details
Main Author:	Chong, Mui Phin
Format:	Thesis
Language:	English
Published:	2018
Subjects:	QD1-999 Chemistry
Online Access:	http://eprints.usm.my/48190/1/CHONG%20MUI%20PHIN_hj.pdf
Tags:	Add Tag No Tags, Be the first to tag this record!

id	my-usm-ep.48190
record_format	uketd_dc
spelling	my-usm-ep.481902021-01-26T02:06:59Z Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors 2018-09 Chong, Mui Phin QD1-999 Chemistry There is a widespread interest in developing the human hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors for the treatment of ischemic/hypoxic diseases. In this study, a new series of 4-oxobutanoic acid analogues was investigated as potential HIF prolyl hydroxylase domain-2 (PHD-2) inhibitors. The compounds were designed based on their binding capabilities to the PHD-2 active sites in a bidentate manner, with the most favorable binding modes in the molecular docking studies using Autodock 4.0 and Accelrys Discovery Studio 4.0. The compounds were synthesized by reacting amines and sulfonamides with succinic anhydride. The synthesized compounds were further characterized using 1D-NMR (1H, 13C), 2D-NMR (COSY, HSQC and HMBC), FTIR, CHN elemental analysis and DIMS. PHD-2 RapidFire assay was further employed to determine the in vitro inhibitory potencies of the 4-oxobutanoic acid analogues against PHD-2. The assay results revealed that compounds F2a and F2b were potent PHD-2 inhibitors, with IC50 values of 242 nM and 160 nM, respectively followed by F3a with IC50 value of 71.2μM. F2a and F2b were found to be more potent in inhibiting PHD-2 than the positive control in the assay, FibroGen’s candidate FG-4592 which is undergoing clinical third phase in treating anemia in patient with chronic kidney disease (CKD). 2018-09 Thesis http://eprints.usm.my/48190/ http://eprints.usm.my/48190/1/CHONG%20MUI%20PHIN_hj.pdf application/pdf en public masters Universiti Sains Malaysia Pusat Pengajian Sains Kimia
institution	Universiti Sains Malaysia
collection	USM Institutional Repository
language	English
topic	QD1-999 Chemistry
spellingShingle	QD1-999 Chemistry Chong, Mui Phin Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
description	There is a widespread interest in developing the human hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors for the treatment of ischemic/hypoxic diseases. In this study, a new series of 4-oxobutanoic acid analogues was investigated as potential HIF prolyl hydroxylase domain-2 (PHD-2) inhibitors. The compounds were designed based on their binding capabilities to the PHD-2 active sites in a bidentate manner, with the most favorable binding modes in the molecular docking studies using Autodock 4.0 and Accelrys Discovery Studio 4.0. The compounds were synthesized by reacting amines and sulfonamides with succinic anhydride. The synthesized compounds were further characterized using 1D-NMR (1H, 13C), 2D-NMR (COSY, HSQC and HMBC), FTIR, CHN elemental analysis and DIMS. PHD-2 RapidFire assay was further employed to determine the in vitro inhibitory potencies of the 4-oxobutanoic acid analogues against PHD-2. The assay results revealed that compounds F2a and F2b were potent PHD-2 inhibitors, with IC50 values of 242 nM and 160 nM, respectively followed by F3a with IC50 value of 71.2μM. F2a and F2b were found to be more potent in inhibiting PHD-2 than the positive control in the assay, FibroGen’s candidate FG-4592 which is undergoing clinical third phase in treating anemia in patient with chronic kidney disease (CKD).
format	Thesis
qualification_level	Master's degree
author	Chong, Mui Phin
author_facet	Chong, Mui Phin
author_sort	Chong, Mui Phin
title	Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
title_short	Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
title_full	Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
title_fullStr	Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
title_full_unstemmed	Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors
title_sort	design, synthesis and characterization of 4-oxobutanoic acid analogues as potential human hypoxia inducible factor (hif) prolyl hydroxylase domain 2 (phd-2) inhibitors
granting_institution	Universiti Sains Malaysia
granting_department	Pusat Pengajian Sains Kimia
publishDate	2018
url	http://eprints.usm.my/48190/1/CHONG%20MUI%20PHIN_hj.pdf
_version_	1747821897664430080

Design, Synthesis And Characterization Of 4-Oxobutanoic Acid Analogues As Potential Human Hypoxia Inducible Factor (Hif) Prolyl Hydroxylase Domain 2 (Phd-2) Inhibitors

Similar Items