Targeting thioredoxin reductase with organometallics

The thioredoxin (Trx) system is a key antioxidant system to the regulation of oxidative stress in cells. Thioredoxin reductase (TrxR) is an enzyme which is central to the Trx system and is upregulated in cancer cells, making it a potential target in anti-cancer therapy. Its active site contains an S...

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Main Author: Koh, Wei Xiang
Other Authors: Leong Weng Kee
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2021
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Online Access:https://hdl.handle.net/10356/152387
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spelling sg-ntu-dr.10356-1523872023-02-28T23:48:31Z Targeting thioredoxin reductase with organometallics Koh, Wei Xiang Leong Weng Kee School of Physical and Mathematical Sciences CHMLWK@ntu.edu.sg Science::Chemistry::Inorganic chemistry::Metals Science::Biological sciences::Biochemistry The thioredoxin (Trx) system is a key antioxidant system to the regulation of oxidative stress in cells. Thioredoxin reductase (TrxR) is an enzyme which is central to the Trx system and is upregulated in cancer cells, making it a potential target in anti-cancer therapy. Its active site contains an S-Se bond (Cys497-Sec498). Since both sulphur and selenium are soft bases, we hypothesise that they may be targeted by organometallic compounds. In this work, two aspects on targeting TrxR with organometallics have been examined: (a) Developing organometallic complexes and derivatives of known drugs that act on TrxR, and (b) mechanistic and kinetic studies on the reaction of organometallic complexes with the S-Se bond. For the first aspect, two groups of organometallic complexes have been studied. The first group are the metallocenyl derivatives of ebselen, a known substrate of TrxR. They are found to inhibit TrxR with an IC50 of 2.5 ± 0.3 µM in a pure protein assay; they have a higher affinity towards TrxR (Km = 0.4 µM) than the natural substrate, Trx. The second is the carbonyl cluster Os3(CO)10(NCMe)2 which has already been shown to induce apoptosis. It is found to interact with selenyl-sulphide and selenides, besides its known reactivity with disulphides and sulfhydryl groups. It inhibits TrxR with an IC50 of 5.3 ± 0.9 mM as a non-substrate inhibitor, is selective even in the presence of high concentrations of GSH, and it has also been shown to inhibit TrxR in cell lysate. These results suggest that the inhibition of TrxR is a potential apoptotic pathway. The second aspect concerns the hypothesis that heterodinuclear organometallic complexes may react selectively with the hetero-dichalcogenide S-Se bond over the homo-dichalcogenide bonds S-S and Se-Se. Mechanistic and kinetic studies on the reactivity of homo/hetero bimetallic Ru and/or Mo complexes (M-M’, where M/M’=Ru/Mo), with two small-molecule mimics for the dichalcogenides, viz., PhEEPh and 1,8-naphthalenedichalcogenides, have been carried out. The reactions are initiated through photocleavage, by visible light, of the metal-metal bonds of the bimetallic complexes. While the Mo-Mo compound reacts faster with Se-containing molecules, the Ru-Ru compound preferred S-containing molecules; the Ru-Mo compound exhibits comparable kinetics for all three E-E’ molecules. A similar trend is observed for the naphthalene derivatives although the rates are significantly slower, postulated to be due to a chelate effect. Doctor of Philosophy 2021-08-06T06:59:44Z 2021-08-06T06:59:44Z 2021 Thesis-Doctor of Philosophy Koh, W. X. (2021). Targeting thioredoxin reductase with organometallics. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/152387 https://hdl.handle.net/10356/152387 10.32657/10356/152387 en 04MNP000387C230 This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Chemistry::Inorganic chemistry::Metals
Science::Biological sciences::Biochemistry
spellingShingle Science::Chemistry::Inorganic chemistry::Metals
Science::Biological sciences::Biochemistry
Koh, Wei Xiang
Targeting thioredoxin reductase with organometallics
description The thioredoxin (Trx) system is a key antioxidant system to the regulation of oxidative stress in cells. Thioredoxin reductase (TrxR) is an enzyme which is central to the Trx system and is upregulated in cancer cells, making it a potential target in anti-cancer therapy. Its active site contains an S-Se bond (Cys497-Sec498). Since both sulphur and selenium are soft bases, we hypothesise that they may be targeted by organometallic compounds. In this work, two aspects on targeting TrxR with organometallics have been examined: (a) Developing organometallic complexes and derivatives of known drugs that act on TrxR, and (b) mechanistic and kinetic studies on the reaction of organometallic complexes with the S-Se bond. For the first aspect, two groups of organometallic complexes have been studied. The first group are the metallocenyl derivatives of ebselen, a known substrate of TrxR. They are found to inhibit TrxR with an IC50 of 2.5 ± 0.3 µM in a pure protein assay; they have a higher affinity towards TrxR (Km = 0.4 µM) than the natural substrate, Trx. The second is the carbonyl cluster Os3(CO)10(NCMe)2 which has already been shown to induce apoptosis. It is found to interact with selenyl-sulphide and selenides, besides its known reactivity with disulphides and sulfhydryl groups. It inhibits TrxR with an IC50 of 5.3 ± 0.9 mM as a non-substrate inhibitor, is selective even in the presence of high concentrations of GSH, and it has also been shown to inhibit TrxR in cell lysate. These results suggest that the inhibition of TrxR is a potential apoptotic pathway. The second aspect concerns the hypothesis that heterodinuclear organometallic complexes may react selectively with the hetero-dichalcogenide S-Se bond over the homo-dichalcogenide bonds S-S and Se-Se. Mechanistic and kinetic studies on the reactivity of homo/hetero bimetallic Ru and/or Mo complexes (M-M’, where M/M’=Ru/Mo), with two small-molecule mimics for the dichalcogenides, viz., PhEEPh and 1,8-naphthalenedichalcogenides, have been carried out. The reactions are initiated through photocleavage, by visible light, of the metal-metal bonds of the bimetallic complexes. While the Mo-Mo compound reacts faster with Se-containing molecules, the Ru-Ru compound preferred S-containing molecules; the Ru-Mo compound exhibits comparable kinetics for all three E-E’ molecules. A similar trend is observed for the naphthalene derivatives although the rates are significantly slower, postulated to be due to a chelate effect.
author2 Leong Weng Kee
author_facet Leong Weng Kee
Koh, Wei Xiang
format Thesis-Doctor of Philosophy
author Koh, Wei Xiang
author_sort Koh, Wei Xiang
title Targeting thioredoxin reductase with organometallics
title_short Targeting thioredoxin reductase with organometallics
title_full Targeting thioredoxin reductase with organometallics
title_fullStr Targeting thioredoxin reductase with organometallics
title_full_unstemmed Targeting thioredoxin reductase with organometallics
title_sort targeting thioredoxin reductase with organometallics
publisher Nanyang Technological University
publishDate 2021
url https://hdl.handle.net/10356/152387
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