새로운 다중 고리 화합물의 합성과 응용

다국어 초록 (Multilingual Abstract)

Part A. Development of Two-Photon Probes for Detection of Intracellular Calcium Ions

Calcium ions act as a secondary messenger of our body to control various functions of the cell. Since changes in calcium ion concentration are closely related to many diseases, detection of intracellular calcium ions level can be one of the approaches to prevent and diagnose the disease before it becomes severe. In order to detect Ca2+ in the cell, we designed two-photon probes targeting cell organelles such as cytosol, mitochondria, and lysosome. For this purpose, we have synthesized the probes possessing a fluorene as a fluorophore and polycarboxylic acids as a calcium receptor. These probes are well characterized for two-photon microscopy to detect the level of calcium ions in each organelle. Therefore, we have designed and synthesized the two-photon probes such as, FBCa-1, FBCa-1-Acid-Amide and FBCa-1-AM-Amide. FBCa-1 shows a 3-fold TPEF enhancement in response to Ca2+, dissociation constant (Kd) of 313 nM and has a fluorene fluorophore with λmax of 485 nm. Additionally, FBCa-1-AM-Amide has a fluorene fluorophore with λmax of 544 nm. Unfortunately, FBCa-1-Acid-Amide shows no enhancement in response to Ca2+.

Part B. An Efficient One-Pot Synthesis of Dibenzoxepino[4,5-c]pyrrole via Aldol Condensation and Etherification

Dibenzoxepino[4,5-c]pyrrole is an important scaffold that shows interesting biological activities. Especially, Asenapine (Saphris®) has been used for the acute treatment of schizophrenia and bipolar disorder. Here, we will present a novel and efficient synthetic method via sequential intramolecular aldol reaction for pyrrole intermediate and SNAr reaction for diaryl ether formation. It is noteworthy that the synthesis of the proposed tetracyclic compound could be achieved by a transition metal-free and one-pot reaction under mild conditions. Therefore, we have designed and synthesized required amide intermediate for one-pot cyclization. Finally, dibenzoxepino[4,5-c]pyrrole derivatives were synthesized successfully through optimized DBU-mediated one-pot cyclization conditions. Further applications of this process are helpful to synthesize various medicinal compounds.

목차 (Table of Contents)

• Part A. 세포 내의 Ca2+을 감지하기 위한 이광자 형광 표지자의 개발
• Ⅰ. 서론
• 1. 생체 내에서의 Ca2+의 역할 ……………………………………………‧…‧‧ 2
• 2. 이광자 형광 …………………………………………………………………‧‧‧ 5
• 3. 형광 감응 메커니즘 (PeT) …………………………………………………‧ 6
• 4. 선행된 Ca2+에 대한 이광자 형광 표지자 연구 …………………‧……‧‧‧ 8
• 5. 연구 방향 및 목적 …………………………………………………………‧‧ 10
• Ⅱ. 결과 및 고찰
• 1. Benzothiazole-Fluorene Based Probes
• 가. 합성 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 12
• 나. FBCa-1의 용매에 따른 단일광자 흡수 및 방출 스펙트럼 ………‧‧ 14
• 다. FBCa-1의 용해도 실험 …………………………………………………‧ 15
• 라. FBCa-1의 해리상수 (Kd) 측정 실험 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 16
• 2. Benzothiazole-carboxamide-Fluorene Based Probes
• 가. 합성 ………………………………………………………………………… 17
• 나. FBCa—1-acid-amide의 용매에 따른 단일광자 흡수 및 방출 스펙트럼 ……………………………‧‧……………………………………………… 20
• 다. FBCa-1-acid-amide의 용해도 및 해리상수(Kd) 측정 실험 ‧‧‧‧‧‧‧‧‧ 21
• 3. 세포 실험 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 23
• Ⅲ. 결론 ………………………………………………………………………‧‧‧‧‧‧‧ 26
• Ⅳ. 실험 방법
• 1. 측정기기 및 시약 ………………………………………………………‧‧‧‧‧‧‧ 28
• 2. 실험 방법 ……………………………………………………………………‧‧ 29
• Ⅴ. 참고문헌 ……………………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 47
• Ⅵ. Part A의 부록………………………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧ 49
• Part B. Aldol Condensation과 Etherification을 통한 Dibenzoxepino[4,5-c]pyrrole의 효율적인 One-Pot 합성
• Ⅰ. 서론
• 1. 녹색 화학 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 66
• 2. One-Pot 반응 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 67
• 3. One-Pot 반응의 응용 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧ 69
• 4. 4중 고리를 포함한 항정신병 약과 Asenapine (Saphris)의 기존 합성 방법 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 73
• 5. 연구 방향 및 목적 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 74
• Ⅱ. 결과 및 고찰
• 1. 역합성 분석 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 76
• 2. 합성
• 가. 카복실산의 합성 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 76
• 나. 아민의 합성 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 77
• 다. One-pot 반응을 위한 Amide 중간체의 합성 ……………………‧‧‧‧ 76
• 라. One-Pot 반응의 최적화 ……………………………………………‧‧‧‧‧‧ 79
• 마. One-Pot 반응을 통한 4중 고리 화합물의 합성 ………………‧‧‧‧‧‧‧ 82
• Ⅲ. 결론 ……………………………………………………………………………‧ 83
• Ⅳ. 실험 방법
• 1. 측정기기 및 시약 …………………………………………………………‧‧‧ 84
• 2. 실험 방법 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 85
• Ⅴ. 참고 문헌 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 94
• Ⅵ. Part B의 부록 ……………………………………………‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 96
• ABSTRACT ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 104