合成iodoacetamide化合物庫以篩選癌症治療新藥物

Abstract

中文摘要 先前我們在Cancer Res. 2009 的報告指出可以使用iodoacetamide-Trp 化合物 共價結合到β-tubulin Cys534 的位置來破壞β-tubulin/CCT-β來當作新穎抗癌法， 特別是具抗藥性癌。在本論文我合成一系列iodoacetamide 化合物來測試它們引 起細胞凋亡之結構-功能關係。這些化合物藉一個修改後的方法來合成：首先將 具氨基化合物和chloroacetyl chloride 作用成chloroacetamide，再將中間物和碘化 鈉作用成最終產物iodoacetamide。這些iodoacetamide 化合物被評估其造成細胞 凋亡之能力，然後經由化合物和β-tubulin 結合的分子模型來解釋其結構-功能關 係。結果顯示這些化合物被預測有相似的結合模式及強度，而它們對HEK29 細 胞也有相似的毒殺效果。

ABSTRACT Previous report has demonstrated the feasibility of targeting β-tubulin around Cys354 by iodoacetamide-Trp to disrupt β-tubulin/CCT-β complex as a new anti-cancer therapy, especially against drug-resistant cancers (Lin et al., Cancer Res. 2009). In the thesis, I have synthesized a series of iodoacetamides to investigate their structure-activity relationship of the cell apoptotic effect. The compounds were synthesized via the modified pathway from the reaction of starting materials containing free amino group with chloro-acetate to form a series of chloroacetamide compounds, followed by reaction with sodium iodine to form the final adducts. The compounds were evaluated for their cell apoptotic effect. Their binding ability with β-tubulin was predicted by computer modeling to rationalize their SAR against cells. The computer modeling revealed similar binding modes and affinity of these compounds with β-tubulin, and they also caused similar apoptotic effect against the HEK-293 cells.