Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4). Issue 2 (15th January 2017)

• Record Type: Journal Article
• Authors: Baumann, Markus; Hussain, Mohammad Musarraf; Henne, Nina; Garrote, Daniel Moya; Karlshøj, Stefanie; Fossen, Torgils; Rosenkilde, Mette M.; Våbenø, Jon; Haug, Bengt Erik
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 2(2017)
• Page Start: 646
• Page End: 657
• Publication Date: 2017-01-15
• Subjects: CXCR4 antagonist -- Peptidomimetic -- Scaffold; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.11.036
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R 1 and R 2, and an aromatic group in R 3 . While contraction/elongation of the guanidine carrying side chains (R 1 and R 2 ) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R 3 ) 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 R 1 substituent.