Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold
Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold
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DOI：
10.1021/jo025615o
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发表时间：
2002-07-12
影响因子：
3.6
通讯作者：
McLellan, TJ
中科院分区：
文献类型：
--
作者：
Dumez, E;Snaith, JS;McLellan, TJ
通过使用一系列酶抑制剂复合物的已知结构作为设计的基础，将通用大环肽结构2设计为一系列蛋白酶的潜在抑制剂。选择靶2的大环性质以降低水解酶促步骤中的熵优势，从而抑制酶的功能。通过分子模拟确定连接基团的性质为苯并恶唑，以保持公认的肽链构象。潜在抑制剂的特异性通过Pi基团的变化（通过掺入苯丙氨酸、天冬氨酸或赖氨酸）来调整，以允许被不同的酶类别识别。目标由双氨基酸衍生物5制备，其本身使用有机锌试剂与碘苯并噻唑7的Pd催化偶联和随后使用HATU的开链衍生物22-24的大环化制备。大环化合物25、28-30和32均不抑制其靶酶。对大环29和胰凝乳蛋白酶相互作用的NMR和MS研究确定化合物29实际上是酶的底物。该结果表明，虽然该设计在鉴定结合的化合物方面部分成功，但由于其大环性质导致的熵优势的降低不足以使29充当抑制剂。
A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the Pi group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.