用以治療亨丁頓舞蹈症及癌症之雙重功能化合物
的設計與合成研究

In 2007, N6-(4-hydroxybenzyl)adenosine (T1-11, 16) was found to exert dual functions, acting as an agonist of adenosine A2A receptor and as an inhibitor of adenosine transporter (ENT1). This cooperative function of T1-11 effectively amplifies the activation of adenosinergic system in synapses. Therefore, T1-11 has potential to be developed to treat Huntington’s disease. The constructed dual-pharmacophore model based on the known ligand structures of A2A receptor and ENT1 suggested the derivatization of hydrophobic moieties at the 5′-position of the lead compound, T1-11, in addition to the modification of 6-NH2 group. Thus, a series of T1-11 analogues were synthesized, and their pharmacological properties and neuroprotective activities were subsequently examined respectively by competitive radioligand binding assay and PC12 cell survival assay. These 5′-modified derivatives of T1-11 and its anisole analogue 19 generally showed somewhat decreased A2A agonism which accompanied by weaker neuroprotective activity. In contrast, these derivatives exhibited slightly better ENT1 inhibitory activity. Utilizing the fusing and merging strategies of the knowledge-based designed multiple ligands (DMLs) approach and Lipinski’s “Rule of Five”, we rationally designed the dual-functional compounds. We have synthesized a series of inhibitors and evaluated their biological activities, including the cytotoxicity and in vitro enzymatic and cell-based assays. All synthesized compounds, except for 137 and 139, exhibited dual inhibitory activities. In particular, 125, 126 and 128 showed selective toxicities against cancer cells. The in vivo animal assay is in progress. Photoprobe 142 was designed based on the structure of 104 and 105. This compound was synthesized and will be used in the photoaffinity labeling experiment in a due course.

並列關鍵字

亨丁頓舞蹈症；腺嘌呤核苷受體；平衡型核苷轉運子

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