合成有潛力的抗癌化合物及利用人類穀氧還蛋白活化之抗癌化合物之前驅物
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2007
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Abstract
人類穀氧還蛋白（human glutaredoxin）為專門且有效地對麩胺基硫蛋白（protein-SSG）進行去麩胺基硫反應（deglutathionylation）的催化蛋白質。論文中主要是針對此還原機制設計藥物，以期釋放抗癌藥物於過度表現Glutaredoxin的癌細胞當中。本文所合成之藥物主要以石膽酸(Lithocholic acid)和鬼臼毒素(podophyllotoxin)為基底藥物進而修飾為人類穀氧還蛋白（human glutaredoxin）的受質，對含-SH基團中間產物測試α(2→3)唾液酸轉移酶之生物活性和乳癌細胞（MDA-MB-231 cell）的活性測試。在實驗室先前合成出具有活性的石膽酸（Lithocholic acid）衍生物中， 首先挑選以石膽酸為骨架所衍生具有Asparate amino acid基團者(Li-O-Asp)為主要發展目標，其對α(2→3)唾液酸轉移酶之IC50約為12 μM，而合成之化合物20中，發現多了-SH基團在尾端不僅可以增加抑制α(2→3)唾液酸轉移酶的活性(IC50約為7.5 μM)，在乳癌細胞（MDA-MB-231 cell）活性測試中亦可增加其殺死乳癌細胞（MDA-MB-231 cell）的能力(23% 抑制效果)，並發現在石膽酸(Lithocholic acid)尾端的羧基團對於增加殺死乳癌細胞之毒性是必須的，而含有酯基尾端會阻礙其對乳癌細胞毒殺能力。
而利用人類穀氧還蛋白（human glutaredoxin）還原機制釋放抗癌藥物於細胞當中之生物實驗測試都陸續在進行中。
Glutaredoxin, a member of the thiol-disulfide oxidoreductase (TDOR) enzyme family, catalyzes the reduction of protein-glutathionyl-mixed disulfides (protein-SSG). Based on the mechanistic pathway, the goal focuses on design and synthesis of inhibitor-glutathionyl-mixed disulfides (inhibitor-SSG), which might be effectively activated by glutaredoxin, overexpressed in several cancer cell lines. Synthesis of podophyllotoxin derivatives and lithocholic acid related compounds was achieved and several of them significantly displayed inhibitory property toward sialyltransferase and also notably inhibited the growth of breast cancer cell. For example, compound 20 is an inhibitor of sialyltransferase with an IC50 value of 7.5 M , meanwhile, it achieved 23% inhibition of MDA-MB-231 growth at the concentration of 20 µM. Furthermore, results demonstrate that the carboxylate group of lithocholic acid derivatives is essential for the inhibition of cancer cell growth and etherification of carboxylate group reduces the ability of cytotoxicity. Currently, study on activation of lithocholic acid-glutathionyl-mixed disulfide by glutaredoxin is still in progress.
Glutaredoxin, a member of the thiol-disulfide oxidoreductase (TDOR) enzyme family, catalyzes the reduction of protein-glutathionyl-mixed disulfides (protein-SSG). Based on the mechanistic pathway, the goal focuses on design and synthesis of inhibitor-glutathionyl-mixed disulfides (inhibitor-SSG), which might be effectively activated by glutaredoxin, overexpressed in several cancer cell lines. Synthesis of podophyllotoxin derivatives and lithocholic acid related compounds was achieved and several of them significantly displayed inhibitory property toward sialyltransferase and also notably inhibited the growth of breast cancer cell. For example, compound 20 is an inhibitor of sialyltransferase with an IC50 value of 7.5 M , meanwhile, it achieved 23% inhibition of MDA-MB-231 growth at the concentration of 20 µM. Furthermore, results demonstrate that the carboxylate group of lithocholic acid derivatives is essential for the inhibition of cancer cell growth and etherification of carboxylate group reduces the ability of cytotoxicity. Currently, study on activation of lithocholic acid-glutathionyl-mixed disulfide by glutaredoxin is still in progress.
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抗癌化合物, 人類穀氧還蛋白, 唾液酸轉移酶, human glutaredoxin, sialyltransferase