초록 ▼

。연구결과
PKC의 DAG binding site에 결합하는 ligand들의 공통된 pharmacophores와 그들의 active conformation을 규명하고, side chain의 구조활성 연구결과 branched chain들이 효소친화력을 증대함을 밝혀냈다. PKC ligand로서 합성된 화합물중 77H-022A, 77H-022B와 IS-360은 PKC-α에 대해 Ki = 11.37, 20.10, 3.37 nM의 강력한 효소친화력를 나타냈으며, 암세포에 대한 검색결과 임상실험 중에 있는 bryostatin과 비교하여

。연구결과
PKC의 DAG binding site에 결합하는 ligand들의 공통된 pharmacophores와 그들의 active conformation을 규명하고, side chain의 구조활성 연구결과 branched chain들이 효소친화력을 증대함을 밝혀냈다. PKC ligand로서 합성된 화합물중 77H-022A, 77H-022B와 IS-360은 PKC-α에 대해 Ki = 11.37, 20.10, 3.37 nM의 강력한 효소친화력를 나타냈으며, 암세포에 대한 검색결과 임상실험 중에 있는 bryostatin과 비교하여 우수한 항암효과을 나타냈으며, 특히 백혈병과 유방암에 선택적인 것으로 조사되었다.

Abstract ▼

Protein kinase C (PKC) represents a family of phospholipid-dependent, serine/threonine-specific protein kinase comprising 12 isozymes. These isozymes are believed to play important roles in cellular signal transduction pathways involved in cellular processes such as cell differentiation, proliferati

Protein kinase C (PKC) represents a family of phospholipid-dependent, serine/threonine-specific protein kinase comprising 12 isozymes. These isozymes are believed to play important roles in cellular signal transduction pathways involved in cellular processes such as cell differentiation, proliferation, modulation of gene expression and multiple-drug resistance (MDR). Therefore, modulators, mostly inhibitors, controlling the enzyme activity have been attracted much attention as potential anticancer agent. Bryostatin, marine natural product, which is under clinical study II phase as anticancer agent is the closest to potential market as PKC ligand.
Most PKC isozymes are activated endogenously by diacylglycerol (DAG) released from the receptor-activated hydrolysis of phosphatidylinositol 4,5-biphosphate or from phosphatidyl choline hydrolysis. PKC is also activated directly by several natural product tumor-promoting agent such as the phorbol ester. The binding site of these ligands on PKC has been identified as a tandem repeat of two cysteine-rich zinc-finger motifs present in the regulatory Cl domain of the enzyme. The pharmacophore-guided approach used in the design of novel PKC ligands was based on the study of the geometry of bioequivalent pharmacophore present in diacylglycerol (DAG) and in the more potent phorbol ester tumor promotors. A number of potent DAG-Iactones were generated by this approach in which the glycerol backbone was constrained into various heterocyclic rings to reduce the entropic penalty associated with DAG binding. This approach culminated with the synthesis of a series of "ultrapotent DAG" molecules that can bind to PKC with low nanomolar affinities. These compounds showed promising antitumor activities against in vitro tumor cell lines, which were correlated proportionally with their binding affinity to the enzyme.

목차 Contents

• 표지 ... 1
• 연구개발 최종보고서 ... 3
• 제출문 ... 4
• 요약문 ... 5
• 영문요약문(SUMMARY) ... 7
• 목차 ... 8
• 제1장 서론 ... 9
• 제2장 국내·외 기술개발 현황 ... 10
• 제3장 연구개발수행 내용 및 결과 ... 11
• 제1절 제 1 세부과제 ... 13
• 제2절 제 2 세부과제 ... 34
• 제3절 제 3 세부과제 ... 65
• 제4장 연구개발목표 달성도 및 대외기여도 ... 90
• 제5장 연구개발결과의 활용성과 및 계획 ... 91
• 가. 계량적 성과 ... 91
• 나. 성과내용기술 ... 91
• 다. 활용계획 ... 92
• 제6장 기타 중요변경사항 ... 92
• 제7장 참고문헌 ... 93
• 최종보고서 요약 (초록) ... 97
• 끝페이지 ... 97