TOTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF NATURAL PRODUCT MIMICS TOWARDS FUNGAL PATHOGENS Open Access
Demeritte, Adrian (Summer 2023)
Abstract
Natural products possess a wide range of bioactivities with potential for therapeutic usage. Often, these natural products are manufactured by certain organisms to make them competitive in their own environments. One can assume that a greater variety of secondary metabolites with novel structures are produced in environments with a larger biodiversity, as to provide producers with a selective advantage against competing organisms, induce antimicrobial effects against pathogenic microbes, or even to act as an adaptation to nonbiological impacts (such as light or elevated temperature). In several cases, these secondary metabolites derive their antimicrobial properties from mimicking natural cofactors. Synthetic chemists have fostered these properties by way of analog development, thereby utilizing novel scaffolds from natural products to reveal, enhance, or maintain bioactivity. The first chapter covers this idea specifically towards antifungal compounds. Pathogenic fungi are particularly capable of resistance development as a large percentage of our current armamentarium targets ergosterol synthesis in some way.
The second chapter covers the synthesis of phenolic bisabolene compounds isolated from deep sea sediment which display impressive activity against the causative agent in black rot in cruciferous vegetables, Alternaria brassicae. As all current inhibitors possess the same mechanism of action, there is a dire need for compounds with novel scaffolds to either overcome point mutations or provide alternative methods to inhibit growth. This chapter goes into the modular synthetic design mimicking the scaffold of the natural product penicaculin A, whose mechanism of action is currently unknown and may possess a novel pharmacophore for Alternaria brassicae inhibition. A key transformation through a theoretical pharmacophore containing intermediate is leveraged for analog development. Results show that peniciaculin A may act as a ubiquinone mimic at the Qo site of the cytochrome bc1 complex.
The third chapter covers the synthesis of 4-hydroxypyridinones which may owe their activity to an underutilized mechanism of action by inhibiting the Qi site of the cytochrome bc1 complex; specifically in their implication towards the invasive indoor pathogen Aspergillus fumigatus. The antifungal activity of 4-hydroxy-2-pyridione class of natural products remains thoroughly unexplored despite promising reports in the literature. This chapter first goes into diverted synthesis of a small group of 4-hydroxypyridinone natural products ilicicolin H, oxysporidinone, sambutoxin and septoriamycin A. The latter hints to the potential for these natural products to adopt different binding poses in the Qi site of the pocket enabling a ‘kingdom switch’. This chapter then covers efforts towards the synthesis of chimeric compounds which may aide in circumventing antifungal resistance through 4-pyridinone compounds which may not only mimic ilicicolin H through a simplified scaffold, but also possess a dual mechanism of action by leveraging the bioactivity of chromene.
Table of Contents
1. Chapter 1: Natural Products
1.1. The importance of discourse in science, from cave walls to island porches 1
1.2. Natural Products: the spices of life are secondary metabolites 2
1.3. Antifungal Compounds 3
1.3.1. Antifungal natural products and derivatives and their mechanism of action 3
1.3.2. Antifungals not based on natural products 6
1.4. Issues with the current toolbox 7
1.5. Why mimic natural products 8
1.6. Examples of antifungals mimicking natural products from the literature 9
1.7. Examples of DTS strategies in the Wuest Lab 11
1.8. Ubiquinone: a lesser utilized target 14
1.9. Chapters 15
1.10. Chapter 1 references 16
2. Chapter 2: Total synthesis and biological evaluation of antifungal phenolic bisabolenes 21
2.1. Introduction 21
2.1.1. Blight and economic impact of fungal pathogens 21
2.1.2. The pesticide problem 22
2.1.3. Penciaculin A: a potential new hope 24
2.1.4. Previous Approaches 26
2.1.4.1. Previous synthesis of penciaculin A 29
2.2. Results and discussion 30
2.2.1. Synthesis by way of Aggarwal borylation (1,2 migration) 30
2.2.2. Synthesis by asymmetric Grignard 33
2.2.3. Synthesis by lithium halogen exchange 35
2.2.3.1. Testing previous methods 35
2.2.3.2. Synthesis of linchpin intermediate 37
2.2.3.3. Lithium halogen exchange 43
2.2.4. Aryl coupling 48
2.2.5. Analog Design 53
2.2.5.1 Ethyl acrylate analogs 55
2.2.5.2 Enone derivatives 56
2.2.6. Antimicrobial activity 57
2.3. Conclusions and future directions 60
2.4. Chapter 2 references 62
3. Chapter 3: Progress towards the total synthesis of 4-hydroxypyridinones 67
3.1. Introduction 67
3.1.1. Silent killers 67
3.1.2. The current toolbox has redundant tools 69
3.1.3. 4-Hydroxypyridinones may provide alternative mechanisms for tackling this issue 69
3.2. Results and discussion 72
3.2.1. Synthesis of pyridinone core 74
3.2.2. Coupling of western fragments 78
3.2.3. C-3 functionalization 80
3.2.3.1. Metalation then insertion into electrophiles 80
3.2.3.2. Suzuki oxidative cleave tandem 82
3.2.4. Revisiting the oxysporidinone western fragment 83
3.2.5. Ongoing strategies for allylboration towards homoallylic alcohols 84
3.2.6. Chimera compounds 86
3.3. Conclusions 92
3.4. Chapter 3 references 92
4. Chapter 4. Experimental details 96
4.1. Fungal growth inhibition assays 96
4.2. Chemistry: General notes 97
4.3. Chemistry Synthesis procedures and characterization 99
4.3.1. Chapter 2 99
4.3.2. Chapter 3 144
4.4. SI references 165
5. Appendix 167
5.1. Appendix chapter 2 167
5.2. Appendix chapter 3 198
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