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Title Page

Abstract

Contents

List of Abbreviations 13

Chapter Ⅰ. Development of Novel Inhibitors of Aurora Kinase A 14

1.1. Introduction 14

1.1.1. Protein Kinase 14

1.1.2. Kinase Inhibitors 16

1.1.3. Aurora Structure 18

1.1.4. Overview of the Aurora Pathway 19

1.1.5. Aurora Kinase Inhibitors 24

1.2. Result and Discussion 26

1.2.1. Target Molecules 1 26

1.2.2. Target Molecules 2 32

1.3. Conclusion 43

Chapter Ⅱ. Development of Novel Inhibitors of Monoamine Oxidase B 44

2.1. Introduction 44

2.1.1. Monoamine Oxidase A and B 44

2.1.2. Monoamine Oxidase B structure 46

2.1.3. Mechanism of the Monoamine Oxidase 47

2.1.4. In Silico Screening 49

2.2. Results and Discussion 50

2.2.1. Target Molecules 3 50

2.2.2. Target Molecules 4 59

2.3. Conclusion 61

Chapter Ⅲ. Experimental Section 62

3.1. Materials and Instrumentation 62

3.2. Synthesis 63

3.2.1. Synthesis of the Piperonylamine Derivatives 63

3.2.2. Synthesis of the Biarylamide Derivatives 77

3.2.3. Synthesis of the Immobilized Compound 14 88

3.2.4. Synthesis of the Bibenzyl Derivatives 92

3.2.5. Synthesis of the Benzothiazole Amide Derivatives 105

3.3. Reference 108

List of Tables

Table 1. in vitro Aurora Kinase A inhibition by analogues of 1 and 1a-r 30

Table 2. in vitro Aurora Kinase A inhibition by analogues of 1s-v 31

Table 3. in vitro Aurora Kinase A inhibition by analogues of 2a-2q 35

Table 4. in vitro Aurora Kinase A inhibition assay 39

Table 5. in vitro Monoamine Oxidase B inhibition by analogues of 3aa-aj 52

Table 6. in vitro Monoamine Oxidase B inhibition by analogues of 3ba-bi 53

Table 7. in vitro Monoamine Oxidase B inhibition by analogues of 3ca-3ck 54

Table 8. in vitro Monoamine Oxidase B inhibition by selected analogues 55

Table 9. in vitro Monoamine Oxidase B inhibition by analogues of 4a-d 60

List of Figures

Figure 1. Structure of a typical protein kinase domain displaying ATP binding site and conserved elements around it (INSR kinase, PDB ID code 1GAG). 15

Figure 2. Representative Type I, II and III kinase inhibitors. 17

Figure 3. Diagram of protein kinase modulators. The diagram represents the kinase domain and modulators, colored as follows: activation loop, green; αC helix, red; and general inhibitor,... 17

Figure 4. Structure of Aurora kinase domains. 19

Figure 5. The upstream regulation of Aurora signaling pathway. 20

Figure 6. The downstream regulation of Aurora signaling pathway and role in mitosis. 22

Figure 7. Regulation of Aurora-A activity by Ran-GTP and TPX2. 23

Figure 8. Some of the known Aurora-B substrates in mitotic cells. 24

Figure 9. Aurora A and cancer. 25

Figure 10. Identification of novel hit compound. (a) Hit compound 1 identified from an ADP-glo assay Aurora kinase A inhibitor screen and analogue 1j. (b) Docking result for 1 bound to... 38

Figure 11. Comparison of the active site of human MAO-B and rat MAO-A. The flavin ring (grey) is in the same orientation from the bottom, and specific inhibitors (black) such as... 45

Figure 12. The crystal structure of human MAO-B. Secondary structure of the human MAO-B dimer. Gray areas indicate insertion into the outer mitochondrial membrane. The domains appear... 46

Figure 13. The oxidation scheme of substrate of MAO B and catalysis of MAOs. 47

Figure 14. Mechanism of dopamine action. 48

Figure 15. Among the compounds that passed in-silico screening, selected compounds tested in vitro Monoamine Oxidase B inhibition 57

Figure 16. Target compound 3 from replacing the keto with amide linkage. 57

Figure 17. Docking result for hits compounds based on MAOB crystal structure (PDB id:2VRM). 58

Figure 18. Target compound 4 from replacing the halogenated phenyl group with fused rings. 60

List of Schemes

Scheme 1. Retrosynthesis of piperonylamine derivatives 1b-e, 1g-r. 26

Scheme 2. Retrosynthesis of piperonylamine derivatives 1a, 1f. 26

Scheme 3. Retrosynthesis of piperonylamine derivatives 1s-v. 27

Scheme 4. Synthesis of piperonylamine derivatives 1, 1b-r. 28

Scheme 5. Synthesis of piperonylamine derivatives 1a, 1f. 29

Scheme 6. Synthesis of piperonylamine derivatives 1s-v. 29

Scheme 7. Retrosynthesis of biarylamide compounds 2b-q. 32

Scheme 8. Retrosynthesis of 1-(3-(pyridin-4-yl)phenyl)ethan-1-one compound 2a. 32

Scheme 9. Synthesis of biarylamide compounds 2b-q. 33

Scheme 10. Synthesis of 1-(3-(pyridin-4-yl)phenyl)ethan-1-one compound 2a. 34

Scheme 11. Retrosynthesis of immobilized compound 14. 40

Scheme 12. Synthesis of immobilized compound 14. 41

Scheme 13. Retrosynthesis of bibenzyl compounds 3aa-ck. 50

Scheme 14. Synthesis of bibenzyl compounds 3aa-cm. 50

Scheme 15. Retrosynthesis of benzothiazol amide compounds 4a-d. 59

Scheme 16. Synthesis of benzothiazol amide compounds 4a-d. 59

초록보기

Aurora kinases are a family of cell division regulators that govern the correct assembly of a bipolar mitotic spindle and the fidelity of chromosome segregation. Their overexpression is associated with genomic instability and aneuploidy, and is frequently observed in cancer.

Accordingly, competitive inhibitors targeting Aurora kinase activity at the ATP-binding site are being investigated for therapeutic purposes. Despite promising pre-clinical data, these molecules display moderate effects in clinical trials and incomplete selectivity. As an alternative approach, protein-protein interaction inhibitors targeting mitotic kinases and their activators can be exploited to achieve increased specificity of action. In this study, a virtual screening of small molecules against the TPX2 interaction site, which also acts as the allosteric site, of AurkA led to the identification of 40 potential inhibitors. in vitro AurkA assay confirmed that a unique scaffold-containing hit compound 1 inhibits Aurora-A in the low micromolar range.

We synthesized diverse analogues of B6 and found an improved analogue that has an equipotent to the reported allosteric inhibitor AurkinA. The novel allosteric inhibitor of AurkA is in a further optimization towards anticancer drugs.

Monoamine oxidase are a family of enzymes that perform oxidation of monoamines. MAOs play vital role in the inactivation of neurotransmitters. MAO-A mainly metabolizes the tyramine and MAO-B catalyzes the oxidative deamination of dopamine. Motor symptoms of parkinson's disease are caused by extensive loss of dopaminergic neurons resulting in nigrostriatal dopamine deficiency. Accordingly, MAO-B inhibitors dopamine degradation in nigrostriatal pathway and could be developed as drugs to modulate Parkinson's disease.

Here, we performed an in silico screening using machine learning method against about 100,000 small molecule library. Amongst the virtual hits, forty-two compounds were purchased and surprisingly 6 of them showed IC50s of less than 100 nM against human MAO-B. All of the 6 hits exhibited ＞100 μM selectivity over human MAO-A. We picked up 2 hits and synthesized analogues to identify selective, potent MAO-B inhibitors.

We wish to demonstrate the powerfulness of AI-driven virtual screening as a tool to streamline the hit identification process and disclose structure-activity relationship of our hit compounds.

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