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Synthesis and cardioprotective activities of green tea polyphenols and their analogues

Synthesis and cardioprotective activities of green tea polyphenols and their analogues
Synthesis and cardioprotective activities of green tea polyphenols and their analogues
Cardiovascular disease is a major killer worldwide and it is becoming clear the significance of our diet in curbing the disease. Green tea is one of the most widely consumed beverages in the world and has recently attracted significant attention in the scientific community for its health benefits. Its consumption has been associated with lower incidences of coronary artery diseases in the Japanese population. This is mainly attributed to its polyphenolic constituents that include epicatechin, epicatechin gallate, epigallocatechin and epigallocatechin gallate. The aim of this research was to synthesise the four major polyphenols present in green as well as analogues. These compounds would then be tested on H9C2 cardiac myoblast cells and neonatal rat cardiomyocytes in order to further understand the structure-activity relationship as well as potentially improve the cardioprotective function of these polyphenols following oxidative stress and ischaemia/reperfusion injury focusing on the expression of STAT-1 and ERK-1/2 proteins. In H9C2 cardiac myoblast cells following the induction of oxidative stress using H2O2, EGCG, EGC and to a minor extent ECG inhibited STAT-1 activation but not ERK- 1/2 phosphorylation suggesting that although the ERK-1/2 pathway gets activated, its downstream activation of STAT-1 is inhibited by the above polyphenols. EC, on the other hand, inhibited ERK-1/2 activation which in turn cannot activate STAT-1. Quantitative assessment of viable cells showed that pretreatment with EGCG resulted in the lowest amount of non-viable cells reducing cell death by 30%. With neonatal rat cardiomyocytes following ischaemia/reperfusion injury, pretreatment with EGCG reduced the amount of non viable cells by 5% but pretreatment with acetylated EGCG at half the concentration of EGCG reduced non-viable cells by 8%. Structure-activity relationships of the green tea polyphenol analogues identified some key aspects in the structures of the polyphenols important in their cardioprotective function. Results indicated that ABD ring system is required for cardioprotective function but the presence of a third OH group in the ring may not be necessary. Substitution of ring C with benzoic and naphthoic rings improved the potency by more than 13-fold compared to EGCG with EC50 values of 1.60 and 0.77 ?M respectively. Further research into these analogues could realise their potential and contribute to the understanding of the cardioprotective activities of green tea. A review on the previous synthesis approaches, isolation and biosynthesis of the green tea polyphenols is presented in Chapter 1 and also the different signalling pathways of interest in this work. An evaluation of the biological activities of the four major polyphenols is provided in Chapter 3. Experimental procedure and characterisation data are in Chapter 5.
Pickard, Olubukunola
1a992b86-f01e-45ee-b018-92e9819c6c33
Pickard, Olubukunola
1a992b86-f01e-45ee-b018-92e9819c6c33
Harrowven, David
bddcfab6-dbde-49df-aec2-42abbcf5d10b

Pickard, Olubukunola (2014) Synthesis and cardioprotective activities of green tea polyphenols and their analogues. University of Southampton, Chemistry, Doctoral Thesis, 224pp.

Record type: Thesis (Doctoral)

Abstract

Cardiovascular disease is a major killer worldwide and it is becoming clear the significance of our diet in curbing the disease. Green tea is one of the most widely consumed beverages in the world and has recently attracted significant attention in the scientific community for its health benefits. Its consumption has been associated with lower incidences of coronary artery diseases in the Japanese population. This is mainly attributed to its polyphenolic constituents that include epicatechin, epicatechin gallate, epigallocatechin and epigallocatechin gallate. The aim of this research was to synthesise the four major polyphenols present in green as well as analogues. These compounds would then be tested on H9C2 cardiac myoblast cells and neonatal rat cardiomyocytes in order to further understand the structure-activity relationship as well as potentially improve the cardioprotective function of these polyphenols following oxidative stress and ischaemia/reperfusion injury focusing on the expression of STAT-1 and ERK-1/2 proteins. In H9C2 cardiac myoblast cells following the induction of oxidative stress using H2O2, EGCG, EGC and to a minor extent ECG inhibited STAT-1 activation but not ERK- 1/2 phosphorylation suggesting that although the ERK-1/2 pathway gets activated, its downstream activation of STAT-1 is inhibited by the above polyphenols. EC, on the other hand, inhibited ERK-1/2 activation which in turn cannot activate STAT-1. Quantitative assessment of viable cells showed that pretreatment with EGCG resulted in the lowest amount of non-viable cells reducing cell death by 30%. With neonatal rat cardiomyocytes following ischaemia/reperfusion injury, pretreatment with EGCG reduced the amount of non viable cells by 5% but pretreatment with acetylated EGCG at half the concentration of EGCG reduced non-viable cells by 8%. Structure-activity relationships of the green tea polyphenol analogues identified some key aspects in the structures of the polyphenols important in their cardioprotective function. Results indicated that ABD ring system is required for cardioprotective function but the presence of a third OH group in the ring may not be necessary. Substitution of ring C with benzoic and naphthoic rings improved the potency by more than 13-fold compared to EGCG with EC50 values of 1.60 and 0.77 ?M respectively. Further research into these analogues could realise their potential and contribute to the understanding of the cardioprotective activities of green tea. A review on the previous synthesis approaches, isolation and biosynthesis of the green tea polyphenols is presented in Chapter 1 and also the different signalling pathways of interest in this work. An evaluation of the biological activities of the four major polyphenols is provided in Chapter 3. Experimental procedure and characterisation data are in Chapter 5.

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Published date: 28 February 2014
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 362977
URI: http://eprints.soton.ac.uk/id/eprint/362977
PURE UUID: 05b26487-2111-46c8-80ec-4932d5d5410a
ORCID for David Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

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Date deposited: 18 Mar 2014 15:43
Last modified: 14 Jul 2018 00:36

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Contributors

Author: Olubukunola Pickard
Thesis advisor: David Harrowven ORCID iD

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