University of St Andrews
Rubanu, Maria Grazia.
The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors.
Degree: PhD, 2019, University of St Andrews
This thesis is focused on the design and synthesis of analogues of thioesters of Co-enzyme A which are involved in many important biosynthetic pathways. Acetyl-CoA is converted into citrate by citrate synthase in the first step of the Krebs cycle that is central for the cellular respiration. Chapter 2 is focused on the successful synthesis of five analogues of acetyl-CoA and their investigation as inhibitors of citrate synthase. This project is based on the finding that Fluorovinyl thioether-CoA (FV-CoA) is a micromolar inhibitor of citrate synthase (Kᵢᵃᵖᵖ = 4.4 µM). Sulfoxide-CoA, with a sulfonyl and a methylene group replacing the carbonyl group and the sulfur atom of acetyl-CoA, was found to be a modest micromolar inhibitor of citrate synthase (11.1 µM), indicating its potential as hydrogen bonding acceptor. The remaining compounds showed poor or too low binding affinity for the enzyme. Although these compounds showed poor inhibitory capacity towards citrate synthase, they could be potential inhibitors of other acetyl-CoA utilizing enzymes, such as malate synthase that catalyzes the conversion of acetyl-CoA into malate. Its activity is correlated to different pathogens pathway (Mycobacterium tubercolosis) and its regulation could potentially prevent the bacterial growth. Chapter 3 describes the attempted synthesis of a fluorovinyl thioacrylate derivative as malonyl-CoA analogue and potential covalent inhibitor of acetyl-CoA carboxylase (ACC). ACC catalyzes the irreversible conversion of acetyl-CoA into malonyl-CoA in the first step of fatty acid synthesis. The regulation of ACC is associated to many cardiovascular diseases such as diabetes, obesity and its inhibition can lead to the development of novel antibiotics for their treatment. Due to the challenging synthesis of the precursor thioester, this malonyl-CoA analogue could not be prepared. Chapter 4 reports the synthesis of α,α,β-trifluoro cyclopropane-CoA and was found to be a poor inhibitor of citrate synthase (Kᵢ = 65.2 µM ). However, this compound has potential to be a covalent inhibitor of citrate synthase and other enzymes such as malate synthase, thus future investigations will be carried out to this purpose. Furthermore, chapter 4 reports the attempted synthesis of an α,α-difluoroethyl thioether-CoA as an acetyl-CoA analogue. This compound bears two electronegative fluorine atoms, thus it could interact electrostatically with the active site residues of citrate synthase through hydrogen bonds, leading to its inhibition. Unfortunately, due to the instability of the difluoro moiety under the enzymatic reaction conditions, this was not converted to the corresponding acetyl-CoA analogue.
Subjects/Keywords: Acetyl-CoA analogues; Enzymatic inhibition; Acetyl-CoA utilising enzymes inhibition; Citrate synthase inhibition
to Zotero / EndNote / Reference
APA (6th Edition):
Rubanu, M. G. (2019). The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors. (Doctoral Dissertation). University of St Andrews. Retrieved from http://hdl.handle.net/10023/18850
Chicago Manual of Style (16th Edition):
Rubanu, Maria Grazia. “The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors.” 2019. Doctoral Dissertation, University of St Andrews. Accessed January 25, 2020.
MLA Handbook (7th Edition):
Rubanu, Maria Grazia. “The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors.” 2019. Web. 25 Jan 2020.
Rubanu MG. The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors. [Internet] [Doctoral dissertation]. University of St Andrews; 2019. [cited 2020 Jan 25].
Available from: http://hdl.handle.net/10023/18850.
Council of Science Editors:
Rubanu MG. The design of acyl modified co-enzyme-A ester analogues as enzyme inhibitors. [Doctoral Dissertation]. University of St Andrews; 2019. Available from: http://hdl.handle.net/10023/18850