合成(E)-5-(2-Radioiodovinyl)arabinosyl Uridine類似物作為皰疹病毒第一型胸腺嘧啶激脢基因探針之研究

Synthesis of (E)-5-(2-Radioiodovinyl)arabinosyl Uridine Analog for Probing HSV-1 Thymidine Kinase Gene

吳建宏(Chien-Hung Wu)

指導教授 ： 俞鐘山

國立清華大學/原子科學院/原子科學系/碩士(2006年)

https://doi.org/10.6843/NTHU.2006.00117

摘要

摘要
癌症基因治療是一種頗具潛力的癌症治療方法。為達到最佳的治療效果，必須先發展能定位基因表現的探針。藉由核醫造影儀器如正電子放射斷層掃瞄(PET) 與單光子放射斷層掃瞄 (SPECT)，非侵入性的示蹤乃得以實現。疱疹病毒基因 (HSV tk) 是目前基因探針系統中最常使用的一種報導基因，而放射性核苷藥物則是此報導基因的示蹤劑。目前，已有許多放射線核苷藥物被製備成功，常見的標誌元素包括氟、溴、碘。有機錫化物是一個非常好的前驅物，可以和放射性碘進行鹵化去金屬反應，因此就造影目的而言三丁基有機錫基便成為我們的首要標靶化合物，本研究是利用商品化之尿嘧啶作為起始物，透過結環反應製備出高熔點且無法以p-anisaldehyde燒出顏色之產物。在這一個步驟不需要額外純化僅須以濾紙過濾再用冰的MeOH沖洗，可以得到乾淨的產物，用此方法所得到的產率高出文獻報導。再利用酸性催化條件進行開環反應，便可得到此阿拉伯醣核苷，利用文獻報導的方式先進行醯化反應以保護氫氧基，利用親電子碘化取代反應可以得到五號碳之碘取代物，利用Heck耦合反應可以把三甲基矽乙炔基引入並得到80%產率，稍後以氟化鉀進行之去矽反應可得到63%產率之產物。三丁基錫可在加熱90 oC的條件下有效率的加成到三鍵，產率為80%，在NMR光譜上，產物只有E-form，這可能是因為立體障礙的關係，在NaOMe的鹼性條件下可以將氫氧保護基移除得到高產率產物，最後用放射性碘化鈉進行氧化取代反應，可以得到80%放射化學產率之碘-125標誌之順五碘烯阿拉伯醣核苷，係透過高效液相層析的放射圖譜計算。

關鍵字

PET ； nucleoside analogy

並列摘要

Abstract

Cancer gene therapy has become a promising approach for treatment of cancer. For achieving the optimized therapeutic effect, a probe which may localize the gene expression, should be developed. By employing nuclear medical instrument such as Positron Emission Tomography and Single Photon Emission Computer Tomography, the noninvasive imaging may be realized. HSV-TK was one of the most used reporter gene and radionuclide was the responsible tracer. Recently, various radionuclides have been prepared. Among them, fluorine, bromine and iodine are frequently used. Organostannan has been widely used in iododestannylation reaction. To our purpose, we are focusing on the preparation of tributyl stannyl nucleoside and its application to radiohalogenation. The commercial uridine was treated with base to provide 2,2’-anhydro uridine 1 with high melting point and no indication of sugar by staining with p-anisaldehyde. Without chromatographic purification, product 1 could be obtained in high yield through washing with cold MeOH. Aarbinosyl uridine 2 could be obtained by ring opening using trace TFA. Following protection by acetylation, iodine could be introduced on C-5 through electrophilic iodination. Iodo group could be replaced by trimethylsilyl ethynyl group in 80% yield. Removal of silyl group was affected by KF. Tributylstannylation was performed under addition of HSnBu3 and yield was 80%. The steric hindrance might account for the unavailability of (Z)-product. Following the removal of acetyl groups with base, a yield of 80% of [125I] (E)-iodovinyl arabinosyluridine could be identified in HPLC chromatogram.

參考文獻

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7. Manuscript “Synthesis of 5-radioiodoarabinosyl uridine analog for probing HSV-1 thymidine kinase gene: An unexpected chelating effect” submitted.