Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

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• 作者：Markus Baumann^a ; Mohammad Musarraf Hussain^a ; ¹ ; Nina Henne^a ; Daniel Moya Garrote^a ; Stefanie Karlshø ; j^b ; Torgils Fossen^a ; Mette M. Rosenkilde^b ; Jon V&aring ; benø ; ^c ; ^{jon.vabeno@uit.no} ; Bengt Erik Haug^a ; ^{bengt-erik.haug@farm.uib.no}
• 关键词：CXCR4 antagonist ; Peptidomimetic ; Scaffold
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：646-657
• 全文大小：1480 K
• 卷排序：25

文摘

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61 μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent.