非肽类小分子蛋白酶体抑制剂的设计、合成及活性研究

The study of peptide proteasome inhibitors has made great progress. However, this kind of drugs has some significant shortcomings, such as high toxicities, lack of efficacy in solid cancer patient and poor in vivo stability et al.. Non-peptide small molecular proteasome inhibitor may be one of an efficient route to overcome these shortcomings. Thus, five kinds of non-peptide small molecular proteasome inhibitors (I-V) will be designed and synthesized in this project based on the combination of our previous research results and the latest advances of proteasome inhibitor. We selected alpha-aminoboronic acid and oxadiazole as warhead, and tetrahydroisoquinoline, diaryl pyrazole and N-aryl sulfonamide as active fragments, which are linked into target compounds（I-V）through the suitable linkers. The suitable linkers will be obtained by the aid of computer aided drug design. All the target compounds will be evaluated for their activities against proteasome and tumor cells, and their structure-activities relationships will be summarized. The promising compounds will be further evaluated for their in vivo antitumor activities, PK properties and acute toxicity. Our goal is to find more potential proteasome inhibitors and open the new research direction of non-peptide small molecular proteasome inhibitors.

肽类蛋白酶体抑制剂的研究已取得了显著进展，但此类抑制剂存在毒副作用大、对实体瘤抑制率低和代谢稳定性不好等缺点。非肽类小分子蛋白酶体抑制剂有望克服肽类蛋白酶体抑制剂的这些缺点。因此，本课题将依据我们前期的研究结果，结合蛋白酶体抑制剂研究的最新进展，选择优秀的氨基硼酸和噁二唑为靶头，四氢异喹啉、多芳基取代吡唑、芳基磺酰胺为活性片段，借助于计算机辅助药物设计筛选出适当的连接臂将其连接，设计、合成五类非肽类小分子蛋白酶体抑制剂（I-V）；在酶和细胞两个水平上评价其活性，总结其构效关系；选择活性好的化合物进行体内活性评价，及初步药代动力学和急性毒性研究，以期发现优秀的非肽类小分子蛋白酶体抑制剂，开辟非肽类蛋白酶体抑制剂研究的新方向。

为克服肽类蛋白酶体抑制剂毒副作用大、对实体瘤抑制率低和代谢稳定性差等缺点，基于本课题组在蛋白酶体抑制剂研究方面的工作基础，结合蛋白酶体抑制剂研究的最新进展，本课题设计并合成了肽呋喃酮、脲拟肽脯氨酸硼酸、四氢异喹啉-噁二唑、和吡唑-硼酸四类共75个非肽小分子蛋白酶体抑制剂。经酶和细胞活性评价，发现脲拟肽脯氨酸硼酸和吡唑-硼酸两类化合物具有显著抗肿瘤活性；选择化合物HG-WYQ-A32和HG-SZZ-A39进行了体内抗肿瘤活性实验，结果表明它们对多发性骨髓瘤（RPMI 8226）的抑制率分别达到了91%和96%，显著优于上市药硼替佐米（52%），且对实体瘤肝癌（Bel7404）的抑制率达到了60%以上，毒副作用明显降低，代谢稳定性明显增强，T1/2 分别为7.2h和7.6h，是非常优秀的候选药物，这些研究结果为进一步研发奠定了很好的基础，为蛋白酶体抑制剂研究的开辟了新方向。深入研究有望克服肽硼酸类蛋白酶体抑制剂的一些缺点和不足。另外，在完成上述工作的过程中，我们还发展了多种有机合成新方法。.基于以上研究结果，我们已申请中国发明专利2项，发表研究论文10篇；培养博士研究生1名，硕士研究生3名。