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계피의 Farnesyl Protein Transferase 저해활성 물질 및 유도체 합성

계피의 Farnesyl Protein Transferase 저해활성 물질 및 유도체 합성
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Studies on Farnesyl Protein Transferase inhibitor isolated from the cortex of Cinnamomum cassia Blume and its derivatives
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대학원 약학과
계피farnesylproteintransferase저해활성 물질유도체
이화여자대학교 대학원
Ras Famesyl Protein Transferase(FPTase) is an enzyme which catalyzes the transfer of the farnesyl group from farnesylpyrophos- phate(FPP) onto cysteine 186 at the C-terminal of the Ras Protein. This is a mandatory process before anchoring to plasma membrane which is critical for triggering ras oncogene toward tumor formation. Therefore, the inhibitor of FPTase have the potential to be used as antittumorigenic agents and there have been many efforts th find out new inhibitors such as peptides or organosynthetic compounds. In the course of a screening program th discover new inhibitors of FPTase from natural sources, 2-hydroxy cinnamaldehyde was isolated for the first time from natural products, the cortex of Cinnamomum cassia Blume, which has been used as antipyretic, hypothermic and aromatic stemachic agents. 2-hydroxy cinnamaldehyde inhibited bovine brain FPTase with an IC_(50) of 24㎍/ml and exhibited significant growth inhibition of colon cancer cell line, HCT 15. In order to investigate the structure-activity relationships, 11 derivatives were synthesized and tested for FPTase inhibitory activity at the concentration of 100㎍/ml. Cinnamic acid, cinnanmic acid methylester, cinnamyl alcohol derivatives showed low inhibitoin activities, compared with cinnamaldehyde derivatives. Among cinnamaldehyde derivatives, the compounds with hydroxyl(OH), chloro(Cl), methylcarboxyl(COOCH_(3)) at 2 position of aromatic ring exhibited relatively high inhibition activity than hydroxyl(OH) at 3,4 position. So, aldehyde(CHO) group, 2-substituted form seems to act as an important functional group in inhibition of FPTase. These results suggest that 2-hydroxy cinnamaldehyde would be used as anticancer agents by innbition of FPTase in colon cancer where mutated ras oncogene is frequently found.;Farnesyl Protein Transferase(FPTase)는 farnesyl pyrophosphate(FPP)의 farnesyl group을 Ras protein의 C-terminal 186 위치에 있는 Cysteine에 이동시키는 과정을 촉매한다. 이 과정을 Ras protein이 세포막에 부착하기 이전에 이루어지는 단계로써, ras oncogene이 암을 유발시키는데 결정적인 역할을 한다. 따라서 FPTase를 저해함으로써 항암효과를 기대할 수 있으며, peptide나 합성화합물 등이 FPTase 저해제로 보고되고 있다. 천연물로부터 새로운 FPTase 저해제를 찾기 위한 검색 과정 중에 계피에서 천연물에서는 처음으로 2-hydroxy cinnamaldehyde를 분리하였다. 계피(Cinnamomum cassia Blume)는 녹나무과(Lauraceae)에 속하는 식물로 전통적으로 발한, 해열, 진토, 방향성 건위효과가 있다고 알려져 있다. 본 실험에서 2-methoxy cinnamaldehyde, coumarin, 2-hydroxy cinnamaldehyde를 분리하였다. 2-hydroxy cinnamaldehyde는 bovine brain FPTase에 대한 IC_(50)가 24㎍/㎖였으며, colon cancer cell line에서 강한 억제효과를 보였다. 2-hydroxy cinnamaldehyde와의 구조활성관계를 보기 위해 11개의 관련 유도체를 합성하였다. 100㎍/㎖에서 FPTase 저해활성을 본 결과 cinnamic acid, cinnamic acid methyl ester, cinnamyl alcohol 유도체는 10% 이하로 cinnamaldehyde 유도체에 비해 낮은 저해활성을 보였다. 또한 cinnamaldehyde 유도체 중 aromatic ring의 2위가 hydroxyl(OH), chloro(Cl), methyl carboxyl(COOCH_(3))로 치환된 유도체는 3, 4위가 hydroxyl(OH)기로 치환된 유도체에 비해 상대적으로 높은 저해도를 보였다. 따라서 aldehyde(CHO)기와 2위의 치환형이 저해활성 발현에 중요한 것으로 보인다. 이러한 결과들로부터, FPTase 저해활성을 보인 2-hydroxy cinnamaldehyde는 oncogenic Ras가 많이 발견되는 결장암의 치료에 유효할 것으로 사료된다.
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