含beta;-氨基酸的硼酸化合物的合成、表征及活性测试
摘要：在各类蛋白酶体抑制剂中，肽硼酸类化合物因其具有高度酶选择性，而一直作为研究的热点。2003年，硼替佐米（bortezomib）成为世界上第一个上市的用于治疗多发性骨髓瘤（multiple myeloma, MM）的二肽硼酸类蛋白酶体抑制剂。Bortezomib属于alpha;，alpha;-二肽硼酸，而beta;-氨基酸作为非天然氨基酸，有着独特的优势，本文通过计算机辅助药物设计的方法，将beta;-氨基酸取代其中一个alpha;-氨基酸作为药物的一个片段，合成出了结构新颖的类似化合物，并测定其蛋白酶体抑制活性。
本课题根据bortezomib与26S蛋白酶体的结合模式以及课题组长期从事蛋白酶体抑制剂研究的相关经验，保留其与蛋白酶体结合的关键硼酸片段，并结合beta;-氨基酸的特点，采用氨基酸替换、生物电子等排等药物设计的方法，设计出结构新颖的蛋白酶体抑制剂；通过Horner–Wadsworth–Emmons反应、不饱和酯的加成、还原、缩合、酯交换等反应，合成出未有文献报道的目标化合物；通过体外酶抑制活性测试考查化合物活性。化合物的结构经1H-NMR、13C-NMR、HRMS 确证。
关键词：蛋白酶体抑制剂、硼酸类化合物、beta;-氨基酸、多肽合成
Synthesis, Characterization and Activity of beta;-Amino Acid-Containing Boronic Acid Compounds
Abstract
Among the various proteasome inhibitors, the peptide boronic acid has been the focus of research because of its high enzyme selectivity. In 2003, bortezomib became the worlds first dipeptide-based proteasome inhibitor for the treatment of multiple myeloma (MM). Bortezomib belongs to alpha;, alpha;-dipeptide boronic acid, and a new structure-like compound is synthesized by the method of computer-aided drug design, in which beta;-amino acid is substituted by one alpha;-amino acid as a fragment of drug, and the proteasome inhibitory activity is shown.
In the present study, based on the binding pattern of bortezomib to the 26S proteasome and the related experience of long-term proteasome inhibitors, the key boronic acid fragments retained by the proteasome were retained, and the amino acid substitution, such as the Horner-Wadsworth-Emmons reaction, the addition of the unsaturated esters, reduction, condensation and transesterification, to synthesize the non-reported targets of the drug-targeted proteasome inhibitors. The compounds will test for in vitro enzyme inhibitory activity. The structures of the compounds will be confirmed by 1H-NMR, 13C-NMR and HRMS.
Key Words: proteasome inhibitors, boronic acid compounds, beta;-amino acids, peptide synthesis
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