設計合成二乙胺基團於醚鏈鍵結之喜樹鹼前驅藥物

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Title:	設計合成二乙胺基團於醚鏈鍵結之喜樹鹼前驅藥物 Design and Synthesis a Diethylamine Group for Ether-linkage of 10-Hydroxycamptothecin Prodrug 喜樹鹼在1966年被發現具有良好抗腫瘤活性，它的作用機制是選擇性地抑制拓撲異構?I，阻斷細胞DNA複製。目前臨床上已有二個喜樹鹼的半合成衍生物Irinotecan and 和Topotecan，用於治療大腸癌，卵巢癌...等癌症，但其對腫瘤無專一性而導致嚴重的副作用。因此，本實驗室開發了兩個喜樹鹼葡萄醣醛酸前驅藥 9-ACG 與 10-HCG ，只會在癌細胞處活化達到標靶作用，減少對正常細胞的毒性。據研究顯示，9-ACG對於水溶性比照10- HCG有100倍的差異，但10-HCG對葡萄醣醛酸?有較好的親和性，為提升10- HCG 的水溶性並降低細胞毒性，設計出10-HCPG，由於所添加之N-methylpiperazine基團的鹼性過強並不穩定，本研究中為了降低基團鹼性過強的問題，將N-methylpiperazine基團換成Diethylamine基團，以利其化合物的穩定，並保有增加水溶性、在血液中穩定、低細胞毒性、酵素親和力，以及對腫瘤有專一性的特性。 Camptothecin was found to have good antitumor activity in 1966. With its selective inhibition of ribozyme DNA topoisomerase I, a series of semisynthetic analogs of camptothecin (Irinotecan and topotecan) were synthesized and shows antitumor activity, but it has no specificity for tumors and causes serious side effects. Therefore, two kinds of camptothecin glucuronic acid precursors (9-ACG and 10-HCG) are designed and synthesized in our laboratory, and the prodrugs will mainly be activated at the cancer cells to achieve Molecular Targeted Therapy. According to research, 9-ACG has a 100-fold advantageous in water solubility of 10-HCG, but 10-HCG has a better substrate for glucuronidase. In order to improve the water solubility of 10-HCG and reduce cytotoxicity, 10-HCPG was designed. But the added N-methylpiperazine group is overly basic and unstable, in order to reduce the problem of over-basicity of the group, the N-methylpiperazine group was replaced with diethylamine group in order to facilitate its compounds are stable and have the characteristics of increasing water solubility, stability in blood, low cytotoxicity, retaining enzyme affinity, and specificity for tumors.
Authors:	洪偉傑
Contributors:	藥學系呂玉玲
Keywords:	癌症前驅藥水溶性 Cancer Prodrug Solubility
Date:	2020
Issue Date:	2022-10-21 10:32:38 (UTC+8)
Relation:	學年度：108， 68頁
Appears in Collections:	[Dept. of Pharmacy] Dissertations and Theses

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