A Tale of Two Chemistries: Dynamics of Delay-Coupled Belousov-Zhabotinsky Oscillators; TrkB Activators: A Review; Synthesis of TrkB Agonists Open Access

Abstract

Part I: Synchronization of oscillatory elements drives many essential biological, chemical, and physical processes. Recent studies have reported complex partial synchronization patterns known as chimera states, which consist of coexisting coherent and incoherent dynamics. By studying small oscillator network systems, researchers hope to gain further insight into the exact principles and mechanisms behind the origin of complex dynamics. This study investigates experimentally the effect of time-delay and network structure on the dynamics of a three ferroin-catalyzed Belousov-Zhabotinsky (BZ) oscillator network and theoretically the effect of time-delay, initial conditions, and heterogeneity in a two-oscillator, ruthenium-catalyzed network on the emergence of complex synchronization patterns. Both experiments and simulations show that small BZ chemical oscillator systems support full and out-of-phase synchronization and period-cycling patterns. However, more complex behaviors, including complex coherent patterns and chaotic chimeras, are unique to the two heterogeneous oscillator system in simulations. Overall, our demonstration of the simplest BZ network that supports chimera states using a realistic model of an experimental system provides a foundation for seeking experimental evidence in simple chemical networks.

Part II: Neurotrophin-receptor interactions are critical for regulating signaling pathways responsible for neuronal growth and maintenance. Altered neurotrophin expression and receptor signaling is correlated with pathological conditions, including Huntington Disease and Alzheimer’s Disease. However, therapeutic application of neurotrophins is restricted by its short in vivo half-life and limited pharmacological selectivity. In this review, we first discuss structural aspects of binding interactions with neurotrophins and Trk receptors. Then, we introduce synthetic small, non-peptide Trk receptor agonists that activate Trk signaling with high potency to demonstrate the potential for these agonists to serve as novel therapeutic options to target underlying disease mechanisms.

Part III: Traumatic blast-related injury, sports injury, or other blunt force trauma to the eye can damage the retina. Current treatments for injuries and diseases to ocular structures and visual systems remain inadequate. The ideal therapy can be quickly administered following injury to an eye in an emergency environment. N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC, n=1) is an N­-acyl serotonin derivative that protects against blast-induced retinal degeneration and vision loss when administered shortly after blast exposure. I have synthesized the HIOC derivative with a 7-membered lactam and made progress towards synthesizing the HIOC analog with a 5-membered lactam. This work is part of the McDonald Lab’s goal of developing HIOC analogs with superior blood brain/retina barrier penetrance, better selectivity for tropomyosin receptor kinase B (TrkB) activation, and higher potency.   

Table of Contents

Table of Contents

Chapter I: Complex Dynamics in Small Networks of Delay-Coupled Belousov-Zhabotinsky Oscillators

1. Introduction.…………………………………………………………………..………………………………….………………… 1

2. Three Oscillator System…………………………………………………………………..………..……..……………..…… 3

           2.1 Experimental Approach………………………………………………………………..……………..…………. 3

                       2.1.1 Preparing Oscillators and BZ Solution……………………………………………………..… 3

                       2.1.2 Arrange Oscillators into Desired Network Structure in BZ Solution…………… 3

                       2.1.3 Image Capture and Analysis……………………………………………………………………… 4

           2.2 Experimental Results………………………………………………………………..……………..……………… 4

3. Two Oscillator System………………………………………………..……………..…………………………………………. 6

           3.1 Model Setup………………………………………………………………..……………..………………………….. 6

           3.2 Simulation Results………………………………………………………………..……………..…………………. 7

                       3.2.1 Homogeneous Oscillators……………………………………………….………………………… 7

                       3.2.2 Heterogeneous Oscillators………………………………………………………………..……… 9

4. Conclusion………………………………………………………………..……………..…………………………………………. 12

5. References………………………………………………………………..……………..………………………………………… 13

 

Chapter II: Structural Aspects of Binding Interactions with Tropomyosin Receptor Kinase B (TrkB)

1. Introduction.…………………………………………………………………..………………………………….……………… 15

2. Neurotrophin and Trk Receptor Structures…………………………………………………………………...…… 17

3. Neurotrophin-Receptor Activation Models…………………………………………………………………...…… 19

4. TrkB Antagonists…………………………………………………………………...…………………………………………… 22

4.1 ANA-12 (N-[2-[(2-oxoazepan-3-yl)carbamoyl]phenyl]-1-benzothiophene-2-carboxamide)……………….…. 22

4.1.1 ANA-12 and Neuronal Survival……………………………………………………………..……………. 24

4.1.2 ANA-12, HIOC, and Ocular Blast-Induced Vision Loss…………………………………………. 24

5. TrkB Agonists…………………………………………………………………...………………………………………………… 25

5.1 N-Acyl Serotonin Amides………………….…………………………………………………………………… 25

5.1.1 N-Acetylserotonin (N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)acetamide, NAS)...………………………………. 25

            5.1.1a Kinetic Characteristics of NAS…………………………………………….……… 25

             5.1.1b Synthesis of NAS.…………………………………………………………………….… 26

             5.1.1c NAS and Traumatic Brain Injury (TBI) ………………………………………… 26

5.1.2 HIOC (N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide)………..………………… 27

            5.1.2a Synthesis of HIOC………..…………………………..…………………….…………. 27

5.1.2b Kinetic Characteristics of HIOC………..…………………………….…………. 28

5.1.2c HIOC and Retinal Damage……..………………………………………………….  28

5.1.2d HIOC and Subarachnoid Hemorrhage (SAH)……..………………………. 29

        5.2 7,8-DHF (7,8-Dihydroxyflavone)…..…………………………..………….…..…………….…..……….. 29

                   5.2.1a 7,8-DHF and Obesity…..…………………………..………….……..………….……..……… 30

                   5.2.1b 7,8-DHF and Huntington’s Disease…..…………………………..………….……..…… 30

                   5.2.1c Chemical Modifications to 7,8-DHF…..………………..………………..………………. 31  

           5.3 LM22A-4 ((N,N’,N’-tris [2-hydroxyethyl])-1,3,5-benzene tricarboxamide) ……….…… 32

                    5.3.1 LM22A-4 and Spinal Cord Injury………………..………………..…………………………. 33

                    5.3.2 LM22A-4 and Hypoxic-Ischemic Stroke………………..………………..………………. 34

           5.4 Deoxygedunin and Deprenyl………………..………………..…………..…………..…………..……….. 34

                    5.4.1a Deoxygedunin and Parkinson’s Disease…………..………………..…………..……… 35

                    5.4.1b Deprenyl and Parkinson’s Disease………..………………..…………………………….. 35

6. Non-TrkB Specific Agonists………..………………..………….………..………………..………….………..………… 36

6.1 LM22B-10 (2-[[4-[[4-[Bis-(2-hydroxy-ethyl)-amino]-phenyl-(4-chloro-phenyl)-methyl]-phenyl]-(2-hydroxy-ethyl)-amino]-ethanol)): TrkB, TrkC agonist..………….………. 36

            6.1.1 LM22B-10 and Neuronal Survival and Process Outgrowth……….…….…….… 37

6.2 Amitriptyline: TrkA, TrkB agonist…….…….…….……….…….…….………….….…….…….………. 37

            6.2.1 Amitriptyline and Huntington’s Disease…….…….…….……….….…….……….…… 37

6.2.2 Amitriptyline and Neurotrophic Activity…….…….…………….….…….……….…… 38

          6.3 DAQ-B1/DMAQ-B1 (Demethylasterriquinone B1): TrkA, TrkB, TrkC agonist………..… 38

                   6.3.1 DMAQ-B1 and Trk Neurotrophin Receptors…….…….…………….….…….………. 39

7. Conclusion………..………………..………….………..………………..………….……….………..………………..……… 40

8. References…………..………………..………….………..………………..………….……….………..………………..…… 40

 

Chapter III: Assessing Lactam Ring Size in N-Acyl Serotonin Derivatives for Treating Trauma-Induced Vision Loss

1. Introduction.…………………………………………………………………..………………………………….………………. 48

2. Experimental Approach………………………………………………………………………………………………...…… 49

           2.1 General Experimental Procedures…………………………………………………………………………. 49

2.2 Synthesis of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-oxopiperidine-3-carboxamide (HIOC)……….……….. 49

            2.2.1 Synthesis of 2-oxopiperidine-3-carboxylic acid………………………………….……. 49

2.2.2 Synthesis of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-oxopiperidine-3-carboxamide (HIOC)……………. 50

2.3 Approach 1: Synthesis of 5-membered lactam through diethyl 2-azidoethylmalonate (7) and ethyl 2-oxo-3-pyrrolidinecarboxylate (8) …………………………….. 51

            2.3.1 Synthesis of diethyl 2-axidoethylmalonate (7)………………………………………… 51

2.3.2 Synthesis of ethyl 2-oxo-3-pyrrolidinecarboxylate (8)…………………………..… 51

            Approach 1: Hydrogenation………………………….………………………….……….… 51

            Approach 2: Reduction of azide to amide by SnCl2 in MeOH……………….. 52

2.4 Approach 2: Synthesis of 5-membered lactam through tert-butyl 2-oxopyrrolidine-1-carboxylate (10), 1-(tert-butyl)-3-ethyl 2-oxopyrrolidine-1,3 dicarboxylate (11), and 1-(tert- butoxycarbonyl)-2-oxopyrrolidine-3-carboxylic acid (12)……………………………………. 52

                       2.4.1 Synthesis of tert-butyl 2-oxopyrrolidine-1-carboxylate (10)…………………… 52

2.4.2 Synthesis of 1-(tert-butyl)-3-ethyl 2-oxopyrrolidine-1,3 dicarboxylate (11)…………………… 53

           2.5 Approach 1: Synthesis of 7-membered lactam through a one-step approach……..… 53

2.6 Approach 2: Synthesis of 7-membered lactam through tert-butyl 2-oxoazepane-1-carboxylate (14), 1-(tert-butyl)-3-ethyl 2-oxoazepane-1,3,dicarboxylate (15), and 1-(tert-butoxycarbonyl)-2-ozoazepane-3-carboxylic acid (16)…………………...…………………………… 54

            2.6.1 Synthesis of tert-butyl 2-oxoazepane-1-carboxylate (14)………...……..……... 54

            2.6.2 Synthesis of 1-(tert-butyl)-3-ethyl 2-oxoazepane-1,3,dicarboxylate (15)… 54

2.6.3 Synthesis of 1-(tert-butoxycarbonyl)-2-ozoazepane-3-carboxylic acid (16)……..…………………….. 55

2.7 Synthesis of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-oxoazepane-3-carboxamide (22)…..………………… 55

2.7.1 Synthesis of tert-butyl 3-((2-(5-hydroxy-1H-indol-3-yl)ethyl)carbamoyl)-2-oxoazepane-1-carboxylate (21)………..…… 55

2.7.2 Synthesis of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-oxoazepane-3-carboxamide (22)……………………………..….… 56

3. Results and Discussion………………………………………………………………………………..………………...…… 56

4. Conclusion…………………………………………..………………………………...…………………………………………… 57

5. References………………………………………..…………………………………...………………………………………….. 58

 

 

Figures and Tables

Chapter I: Complex Dynamics in Small Networks of Delay-Coupled Belousov-Zhabotinsky Oscillators

Figure 1………………………………………………………………..……………..…………………………………………………… 4

Figure 2………………………………………………………………..……………..…………………………………………………… 4

Figure 3………………………………………………………………..……………..…………………………………………………… 5

Figure 4………………………………………………………………..……………..…………………………………………………… 5

Figure 5………………………………………………………………..……………..…………………………………………………… 7

Figure 6………………………………………………………………..……………..…………………………………………………… 8

Figure 7………………………………………………………………..……………..…………………………………………………… 9

Figure 8………………………………………………………………..……………..…………………………………………………… 9

Figure 9………………………………………………………………..……………..…………………………………………………. 11

 

Chapter II: Structural Aspects of Binding Interactions with Tropomyosin Receptor Kinase B (TrkB)

Table 1………………………………………………………………..……………..………………………………………………….. 16

Figure 1………………………………………………………………..……………..…………………………………………………. 17

Figure 2………………………………………………………………..……………..…………………………………………………. 21

Figure 3………………………………………………………………..……………..…………………………………………………. 22

Figure 4………………………………………………………………..……………..…………………………………………………. 23

Scheme 1…………………………………………………………..……………..……………………………………………………. 24

Scheme 2…………………………………………………………..……………..……………………………………………………. 25

Scheme 3…………………………………………………………..……………..……………………………………………………. 26

Scheme 4…………………………………………………………..……………..……………………………………………………. 27

Scheme 5…………………………………………………………..……………..……………………………………………………. 28

Scheme 6…………………………………………………………..……………..……………………………………………………. 30

Figure 5………………………………………………………………..……………..…………………………………………………. 31

Scheme 7…………………………………………………………..……………..……………………………………………………. 31

Scheme 8…………………………………………………………..……………..……………………………………………………. 32

Figure 6…………………………………………………………..……………..……………………..……………………………….. 32

Scheme 9…………………………………………………………..……………..……………………………………………………. 33

Scheme 10…………………………………………………………..……………..………………………………………………….. 34

Scheme 11…………………………………………………………..……………..………………………………………………….. 35

Scheme 12…………………………………………………………..……………..………………………………………………….. 37

Scheme 13…………………………………………………………..……………..………………………………………………….. 39

 

Chapter III: Assessing Lactam Ring Size in N-Acyl Serotonin Derivatives for Treating Trauma-Induced Vision Loss

Figure 1………………………………………………………………..……………..…………………………………………………. 48

Scheme 1…………………………………………………………..……………..……………………………………………………. 49

Scheme 2…………………………………………………………..……………..……………………………………………………. 49

Scheme 3…………………………………………………………..……………..……………………………………………………. 50

Scheme 4…………………………………………………………..……………..……………………………………………………. 51

Scheme 5…………………………………………………………..……………..……………………………………………………. 51

Table 1……………………………………………………….……..……………..……………………………………………………. 52

Scheme 6…………………………………………………………..……………..……………………………………………………. 52

Scheme 7…………………………………………………………..……………..……………………………………………………. 53

Scheme 8…………………………………………………………..……………..……………………………………………………. 54

Scheme 9…………………………………………………………..……………..……………………………………………………. 55

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	TrkB Chemical Oscillators Organic Synthesis
Committee Chair / Thesis Advisor	Simbarashe Nkomo, Emory University Frank E. McDonald, Emory University
Committee Members	David Lynn, Emory University Devon Goss, Emory University

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