設計及合成具有四位及六位取代的嘧啶核苷作為具有潛力的ODCase抑制劑
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2008
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本論文針對 orotidine 5’-monophosphate decarboxylase (ODCase) 設計 6-aryluridine 衍生物，希望合成出對 ODCase 具有生物活性的化合物，並作為可能的 ODCase 抑制劑。
首先，期望利用 C-C 鍵的生成，得到 6-aryluridine 衍生物。我們使用文獻方法，合成 6-halouridine 衍生物，再進行 Suzuki coupling 及 Stille coupling 反應，但實驗結果未能得到預期的產物。
接者，我們改用 click chemistry 來合成 6-aryluridine 衍生物。以 1,3-dimethyl-6-chlorouracil 與 NaN3 進行親核性取代反應得到 6-azido-1,3-dimethyluracil ，再與 acetylene 進行 Huisgen 1,3-dipolar 環化加成反應，得到具有 1,2,3-triazole 取代的 uracil 衍生物。
另外，希望以相同的方法合成出具有 1,2,3-triazole 的 uridine 衍生物。以醣已保護的 uridine 衍生物作為反應起始物，與 LDA 作用，再與 iodine 反應得到 6-iodouridine 衍生物，再利用模型反應的條件可以得到預期的 6-(1,2,3-triazolyl)uridine 衍生物。後續利用三氟醋酸去除 tert-butyldimethylsilyl 及 isopropylidene 保護，由於產物的不穩定，未能得到預期的 triazolyluridine 產物。在本論文中，我們成功地利用 click chemistry 製備 6-(1,2,3-triazolyl)uridine 衍生物，醣的去保護方法仍需要再深入研究。
Abstract We have designed 6-aryluridine derivatives targeting on orotidine 5’-monophosphate decarboxylase (ODCase) as potential inhibitors and chemotherapeutic agents. We anticipated to utilize C-C bond formation approach to introduce the 6-aryl substituent on uridine. 6-Halouridine derivatives were prepared by literature procedures. However, both Suzuki coupling and Stille coupling reaction failed to afford the desired 6-aryluridine derivatives. We then utilized click chemistry to prepare 6-aryluridine derivatives. 1,3-Dimethyl-6-chlorouracil was treated with sodium azide to give 6-azido-1,3-dimethyluracil by nucleophilic substitution reaction. Huisgen 1,3-dipolar cycloaddition reaction of the azidouracil with acetylene in the presence of Cu(I) catalyst afforded 1,2,3-triazole substituted uracil in good yield. The same approach was applied to the synthesis of 1,2,3-triazole substituted uridine derivatives. The suger-protected uridine derivative was used as a starting material and was treated with lithium diisopropylamide, and then was reacted with iodine to give the corresponding 6-iodouridine derivative. The azido group was introduced by nucleophilic substitution reaction. The 6-azidouridine derivative underwent 1,3-dipolar cycloqddition to afford the corresponding 1,2,3-triazole. The removal of tert-butyldimethylsilyl and isopropylidene group with trifluoroacetic acid was unsuccessful to give the desired product. We have successfully prepared 6-(1,2,3-triazolyl)uridine derivative. The deprotection of suger moiety needs further investigation.
Abstract We have designed 6-aryluridine derivatives targeting on orotidine 5’-monophosphate decarboxylase (ODCase) as potential inhibitors and chemotherapeutic agents. We anticipated to utilize C-C bond formation approach to introduce the 6-aryl substituent on uridine. 6-Halouridine derivatives were prepared by literature procedures. However, both Suzuki coupling and Stille coupling reaction failed to afford the desired 6-aryluridine derivatives. We then utilized click chemistry to prepare 6-aryluridine derivatives. 1,3-Dimethyl-6-chlorouracil was treated with sodium azide to give 6-azido-1,3-dimethyluracil by nucleophilic substitution reaction. Huisgen 1,3-dipolar cycloaddition reaction of the azidouracil with acetylene in the presence of Cu(I) catalyst afforded 1,2,3-triazole substituted uracil in good yield. The same approach was applied to the synthesis of 1,2,3-triazole substituted uridine derivatives. The suger-protected uridine derivative was used as a starting material and was treated with lithium diisopropylamide, and then was reacted with iodine to give the corresponding 6-iodouridine derivative. The azido group was introduced by nucleophilic substitution reaction. The 6-azidouridine derivative underwent 1,3-dipolar cycloqddition to afford the corresponding 1,2,3-triazole. The removal of tert-butyldimethylsilyl and isopropylidene group with trifluoroacetic acid was unsuccessful to give the desired product. We have successfully prepared 6-(1,2,3-triazolyl)uridine derivative. The deprotection of suger moiety needs further investigation.
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ODCase