Development of Serotonin Receptor Modulators and Carbapenem-based Fluorogenic Probes
- 주제(키워드) serotonin , carbapenem
- 발행기관 고려대학교 대학원
- 지도교수 김학중
- 발행년도 2020
- 학위수여년월 2020. 2
- 학위구분 박사
- 학과 대학원 화학과
- 원문페이지 253 p
- UCI I804:11009-000000127474
- DOI 10.23186/korea.000000127474.11009.0000947
- 본문언어 영어
초록/요약
Serotonin (5-HT) is one of the major excitatory neurotransmitters and involved in various functions such as appetite, pain, libido, and biorhythm. Serotonin receptors, mediated by serotonin, have been classified into seven subfamilies (5-HT1 to 5-HT7). Among them, 5-HT2C receptor is associated with diverse brain diseases such as obesity, anxiety, depression, schizophrenia and Parkinson's disease. However, it is difficult to develop therapeutic agents targeting the 5-HT2C receptor because it is structurally similar to 5-HT2A and 5-HT2B belonging to the same 5-HT2 family. To obtain more selective and potent 5-HT2C ligands, we have designed and synthesized a series of optically active pyrimidine derivatives 3 and disubstituted pyrimidines 4. Through the in vitro cell-based assay and binding assay, it was found that the absolute stereochemistry of methyl group on the phenethyl moiety of compounds 3 has a significant effect on their binding affinity and selectivity to 5-HT2C. In addition, among the disubstituted pyrimidine derivatives 4 containing different cyclic amines, 4aa exhibit the highest binding affinity. Based on high selectivity to 5-HT2C over other 5-HT subtypes along with drug-like property results including plasma stability, microsomal stability, and CYP inhibition, compound 4aa was finally identified as a potent and selective 5-HT2C agonist.
more초록/요약
Carbapenem, the antibiotic of the last resort, is very effective in treating infections of gram-negative bacteria due to its high activity against broad range of bacterial pathogen and excellent stability against most β-lactamases. However, due to the widespread use of these antibiotics, the emergence of carbapenem-resistant Enterbacteriaceaes (CREs) is spreading rapidly around the world. Therefore, there is a need for the development of efficient and accurate methods for detecting carbapenemase-producing CREs (CP-CREs) for the control and treatment of bacterial infections. Among various efforts to detect CP CREs efficiently, fluorescence-based detection methods have recently received considerable attention due to their unique properties, including high sensitivity, reliability and technical simplicity. In this respect, we designed and synthesized novel fluorescence carbapenemase substrates included the carbapenem core structure as an enzyme recognition moiety, a cleavage linker and a fluorescence dye. First, we synthesized the fluorogenic probes with different types of cleavable linkers such as benzyl ether, carbamate and amine starting from hydroxymethyl carbapenem 6a and hydroxylallyl carbapenem 6b as key intermediates. For the purposes of increasing the stability of 14a and detection efficiency against carbapenemases, derivatives 14c-j containing various substituents at the ortho- or meta position in benzyl ether linker were synthesized. In addition, the substrates 42 and 45 with fluorescence dyes such as naphthalimide 32 and styryl tyrosine 37 were synthesized as ratiometric probes. The results of stability test in PBS buffer (pH 7.4) and enzyme assay of synthesized probes indicated that the substrate 14a showed good specificity and selectivity to carbapenemases. In addition, the probe 14h containing ortho-methoxy substituent in benzyl position showed high fluorescent signals in the carbapenemase assays. Therefore, these compounds would be practical fluorogenic probes for detecting CP-CREs selectively.
more목차
PART 1
Synthesis and Biological Evaluation of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators
ABSTRACT ······················································································· X
Ⅰ. INTRODUCTION ········································································· 2
1.1. Serotonin ······························ ·················································· 2
1.2. Serotonin Receptors (5-HTRs) ················································· 4
1.3. Serotonin 2C Receptor (5-HT2CR) Modulators ······················· 8
Ⅱ. RESULT AND DISCUSSION ························································· 9
2.1. Ligand Design ·········································································· 9
2.2. Synthesis of 5-HT2CR Ligands ················································ 10
2.3. Biological Evaluation ······························································ 17
2.4. Molecular Docking Study ············· ········································· 24
Ⅲ. CONCLUSION ··········································································· 27
Ⅳ. EXPERIMENTAL SECTION ························································· 28
REFERENCE ······················································· ···························· 71
ABSTRACT IN KOREAN ··················· ·············································· 237
PART 2
Development of Carbapenem-based Fluoregenic Probes for Detection of Carbapenemase Producing Bacteria
ABSTRACT ····················································································· XI
Ⅰ. INTRODUCTION ······································································· 77
1.1. Carbapenem ·········································································· 77
1.2. Carbapenem Resistance Mechanism ··································· · 79
1.3. Carbapenemases ··································································· 82
1.4. Current Detection Methods ·················································· 89
1.5. Previous Research on Fluorescence-Based Assays ················· 93
Ⅱ. RESULT AND DISCUSSION ······················································· 95
2.1. Design of Carbapenem-Based Fluorogenic Probes ················ 95
2.2. Development of Carbapenem-Based Fluorogenic Probes ······ 96
Ⅲ. CONCLUSION ·········································································· 121
Ⅳ. EXPERIMENTAL SECTION ························································ 122
REFERENCE ························································ ·························· 229
ABSTRACT IN KOREAN ·································································· 238
