臺灣博碩士論文加值系統

本論文報導4-substituted 7-(3-fluoro-4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidines 11–40之合成與其抗癌活性評估。本人以3-fluoro-4-methoxybenzaldehyde (5)和4-methoxybenzaldehyde (8)為起始物，以NaBH4對其上之formyl group進行reduction，可生成其對應之醇類6a與9，產率分別為93%與88%。本人亦使methylmagnesium bromide與5進行反應，使其生成二級醇6b，產率為96%。化合物6a與9可利用SOCl2將其上之hydroxyl group轉換成chloro atom，生成benzylic chloride 7a與10，產率分別為95%與94%，而化合物6b可與oxalyl chloride反應生成benzylic chloride 7b。化合物7a、7b及10可對市售藥品4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4) 進行alkylation，生成N-7 alkylated 4-chloro-7H-pyrrolo[2,3-d]pyrimidines 3a–c中間體，產率為23–93%。最後本人於中間體3a–c之C–4的位置引入alkoxy、hydroxyl、amino、alkylamino、alkylthio、alkyl、vinyl group等取代基，即可生成各式之4-substituted 7-(3-fluoro-4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidines 11–40，產率為20–99%，其中化合物35在其濃度為1.0 µM時，降低MDA-MB-231和MDA-MB-468乳癌細胞之cell viability，分別為控制組之9.2%和1.1%。

In this thesis, I reported the synthesis and antiproliferative activity of of 4-substituted 7-(3-fluoro-4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidines 11–40. 3-Fluoro-4-methoxybenzaldehyde (5) and 4-methoxybenzaldehyde (8) served as the staring materials and were reduced with NaBH4 to afford the corresponding alcohols 6a and 9 in 93% and 88% yields, respectively. Reaction of 8 with methylmagnesium bromide gave the secondary alcohol 6b in 96% yield. The hydroxy group in 6a, 6b, and 9 was transformed into a chloro atom by SOCl2 or (COCl)2 to give the desired benzylic chlorides 7a, 7b, and 10 in 94–95% yields. Compounds 7a, 7b, and 10 were allowed to react with commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4) to give N-7 alkylated 4-chloro-7H-pyrrolo[2,3-d]pyrimidines 3a–c as the key intermediates in 23–93% yields. Intermediates 3a–c were eventually reacted with alkoxy, hydroxyl ,amino, alkylamino, alkylthio, alkyl, vinyl group at their C–4 position to give the desired 11–40 in 20–99% yields. Among 11–40, compound 35 displayed the best in vitro activities. At the concentration of 1.0 µM, it redcued the cell viabilities of MDA-MB-231 and MDA-MB-468 breast cancer cells to 9.2% and 1.1%, respectively.

中文摘要……………………………………………………………………………I
Abstract …………………………………………………………………………II
謝誌…………………………………………………………………………………III
一、簡介………………………………………………………………………………2
1.Tublin生物功能…………………………………………………………2
2.微管蛋白抑制劑…………………………………………………………………3
3.微管蛋白抑制劑與微管蛋白作用的位置………………………………………4
4.Vascular Disrupting Agent………………………………………………6
5. Colchine binding site目前臨床作用研究情形………………………7
6. T138067自殺型抑制劑…………………………………………………………8
二、藥物設計………………………………………………………………………10
三、結果與討論……………………………………………………………………………………12
1.關鍵中間體4-chloro-7-(3-fluoro-4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (3a)之合成……………………………………………12
2. 4-Substituted -7-(3-fluoro-4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine衍生物之合成 …………………………………………12
3.中間體4-chloro-7-[1-(3-fluoro-4-methoxyphenyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (3b)之合成…………………………………16
4. 4-Substituted-7-[1-(3-fluoro-4-methoxyphenyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidine衍生物之合成………………………………17
5. 中間體4-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (3c)之合成………19
6. 化合物11–40抗癌活性測試………………………………………………20
四、結論…………………………………………………………………………25
五、實驗步驟……………………………………………………………………26
六、參考文獻……………………………………………………………………46
七、光譜數據……………………………………………………………………49

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