Isolation and structural study on new phospholipase C inhibitors originated from natural sources새로운 포스포리파제 C 저해 천연물질의 분리 및 구조에 관한 연구

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Phosphoinositide specific phospholipase C (PI-PLC) plays a pivotal role in the intracellular signal transduction induced by a variety of extracellular stimuli. In the course of screening programs for PLC inhibitors from natural sources such as fungal isolates and medicinal plants, eleven compounds were isolated. Compound 1, 2 and 3 were isolated by the bioassay-guided purification from an unidentified fungus MT51005. By the various NMR techniques such as $^1H$-NMR, $^{13}C$-NMR, DEPT, $^{13}C-^1H$ COSY, NOESY, and HMBC, these compounds were determined as anguillosporal (1) (2,4-dihydroxy-3-ethyl-6-(1``-methylpentyl)-benzaldehyde), CRM-51005 (2) (2, 4-dihydroxy-3-ethyl-6-(1``-methyl-1``-pentenyl)-benzaldehyde) and CRM-51006 (3) (1-(3``-ethyl-2``, 4-dihydroxyphenyl)-2-methyl-1-hexanone). Among these compounds, CRM-51005 (2) and CRM-51006 (3) were identified as new compounds. When these compounds were evaluated for the ability to inhibit PLCγ1 activity in vitro, all of compounds inhibited PLCγ1 activity in dose-dependent manner. The compound 3 showed the most potent activity with an $IC_{50}$ of 2 ㎍/ml (8 μM), whereas 1 and 2 showed the similar inhibitory activity with the $IC_{50}$ of 4.7 ㎍/ml (18.8 μM). When the effects of these compounds on the PDGF-induced accumulation of inositol phosphates in PLCγ1-overexpressing NIH3T3 fibroblasts (NIH3T3γ1) cells were examined, 1 and 3 showed the similar inhibitory activity with the $IC_{50}$ of 0.8 ㎍/ml (3.2 μM). But, 2 showed slightly less activity with an $IC_{50}$ of 3.2 ㎍/ml (12.8 μM). The compound 2 showed the potent activity against T47D (breast cancer), PC-3 (prostate cancer) and OVCAR-4 (ovary cancer) among the examined human cancer cell lines. Especially, 2 showed the most potent growth inhibition (GI) against OVCAR-4 with the $GI_{50}$ values of 0.359 ㎍/ml. Eight isoflavonoids were isolated from ${CH_2Cl_2}$ layer of Erythrina senegalensis (Leguminosae). By the various NMR techniques and physico-chemical prop...
Advisors
Kim, Yong-Hae김용해
Description
한국과학기술원 : 화학과,
Publisher
한국과학기술원
Issue Date
1999
Identifier
151518/325007 / 000945248
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 화학과, 1999.2, [ xii, 163 p. ]

Keywords

CRM-51005 and 51006; Erysenegalensein N and O; Natural sourses; 포스포리파제 C; 저해제; 씨알렘 51005와 51006; 에리세네갈렌세인 엔과 오; 천연물; Phospholipase C; Inhibitors

URI
http://hdl.handle.net/10203/31509
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=151518&flag=dissertation
Appears in Collection
CH-Theses_Ph.D.(박사논문)
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