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Resveratrol esters: synthesis, structure and biologiacal activity

Alicja Urbaniak

Abstract

Resveratrol is a common polyphenol widely occurring in many plans species. It is known from numerous biological activities where the most significant is its cancer preventing property. However, its wider application is limited due to poor water solubility, low stability and weak bioavailability. To overcome this limitations I designed and synthesized novel resveratrol triesters. Because of their non-polar character and hence facilitated transportation across lipid bilayers esters constitute one of the most promising derivatives. I hypothesized two possible scenarios of their action. Firstly, the activity may be derived from novel molecule itself. Moreover, due to the possible hydrolysis after passing through biological membranes esters will release parent, unbonded molecules. In this way triesters may constitute the transporters for easier resveratrol delivery. My first goal was to optimize the procedure for convenient and efficient synthesis of resveratrol triesters. After detailed screening of multiple reaction conditions I found the application of microwave heating for the direct reaction of resveratrol with acyl chloride in acetonitrile in the presence of DBU and DMAP to be the most effective. In the next step, according to the optimized protocol I synthesized the representative library of twelve aromatic and aliphatic triesters of resveratrol. One aliphatic (resveratryl triisobutyrate) and one aromatic (resveratryl tri-2,6-dichlorobenzoate) example were submitted to crystal structure analysis performed by Prof. Urszula Rychlewska research group. Acute lymphoblastic leukemia is the most common childhood malignancy. In order to find new anti-leukemic agents, I evaluated in vitro the series of novel resveratrol triesters towards activity against primary acute lymphoblastic leukemia cells. Three from all of the compounds screened, namely: resveratryl triacetate (IC50 = 3.4 μM), resveratryl triisobutyrate (IC50 = 5.1 μM) and resveratryl triisovalerate (IC50 = 4.9 μM) were characterized by approximately two to three times lower IC50 values than unbonded resveratrol (IC50 = 10.5μM). Further detailed studies revealed that those three drugs blocked cell cycle progression at G1 phase after 48 h incubation, to finally case cell death (indicated by the significant amount of cells in SUB-G1 phase) after 96 h and 120 h. These promising compounds showed the characteristic features of apoptosis like increased level of p53 protein.
Record ID
UAM7748050ffd96479284b8f4e45536986b
Diploma type
Doctor of Philosophy
Author
Alicja Urbaniak (SNŚ/WC/FoC) Alicja Urbaniak,,
Title in Polish
Estry resweratrolu: synteza, struktura i aktywnosć biologiczna
Title in English
Resveratrol esters: synthesis, structure and biologiacal activity
Language
pl Polish
Certifying Unit
Faculty of Chemistry (SNŚ/WC/FoC)
Discipline
chemistry / (chemical sciences domain) / (physical sciences)
Scientific discipline (2.0)
6.5 chemical sciences
Defense Date
17-07-2017
End date
17-07-2017
Supervisor
URL
http://hdl.handle.net/10593/18630 opening in a new tab
Keywords in English
Resveratrol esters, acute lymphoblastic, leukemia, anti-cancer activity
Abstract in English
Resveratrol is a common polyphenol widely occurring in many plans species. It is known from numerous biological activities where the most significant is its cancer preventing property. However, its wider application is limited due to poor water solubility, low stability and weak bioavailability. To overcome this limitations I designed and synthesized novel resveratrol triesters. Because of their non-polar character and hence facilitated transportation across lipid bilayers esters constitute one of the most promising derivatives. I hypothesized two possible scenarios of their action. Firstly, the activity may be derived from novel molecule itself. Moreover, due to the possible hydrolysis after passing through biological membranes esters will release parent, unbonded molecules. In this way triesters may constitute the transporters for easier resveratrol delivery. My first goal was to optimize the procedure for convenient and efficient synthesis of resveratrol triesters. After detailed screening of multiple reaction conditions I found the application of microwave heating for the direct reaction of resveratrol with acyl chloride in acetonitrile in the presence of DBU and DMAP to be the most effective. In the next step, according to the optimized protocol I synthesized the representative library of twelve aromatic and aliphatic triesters of resveratrol. One aliphatic (resveratryl triisobutyrate) and one aromatic (resveratryl tri-2,6-dichlorobenzoate) example were submitted to crystal structure analysis performed by Prof. Urszula Rychlewska research group. Acute lymphoblastic leukemia is the most common childhood malignancy. In order to find new anti-leukemic agents, I evaluated in vitro the series of novel resveratrol triesters towards activity against primary acute lymphoblastic leukemia cells. Three from all of the compounds screened, namely: resveratryl triacetate (IC50 = 3.4 μM), resveratryl triisobutyrate (IC50 = 5.1 μM) and resveratryl triisovalerate (IC50 = 4.9 μM) were characterized by approximately two to three times lower IC50 values than unbonded resveratrol (IC50 = 10.5μM). Further detailed studies revealed that those three drugs blocked cell cycle progression at G1 phase after 48 h incubation, to finally case cell death (indicated by the significant amount of cells in SUB-G1 phase) after 96 h and 120 h. These promising compounds showed the characteristic features of apoptosis like increased level of p53 protein.

Uniform Resource Identifier
https://researchportal.amu.edu.pl/info/phd/UAM7748050ffd96479284b8f4e45536986b/

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