Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands

Maxwell M. Sakyiamah, Takuya Kobayakawa, Masayuki Fujino, Makoto Konno, Tetsuo Narumi, Tomohiro Tanaka, Wataru Nomura, Naoki Yamamoto, Tsutomu Murakami, Hirokazu Tamamura

研究成果: Article査読

10 被引用数 (Scopus)


The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5–7.5 Å showed potent binding affinity selective for CXCR4 with IC 50 values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC 50 s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.

ジャーナルBioorganic and Medicinal Chemistry
出版ステータスPublished - 15 3月 2019


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