Low-Molecular-Weight CXCR4 Ligands with Variable Spacers

Authors

  • Dr. Tetsuo Narumi,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Dr. Haruo Aikawa,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Dr. Tomohiro Tanaka,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Chie Hashimoto,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Dr. Nami Ohashi,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Dr. Wataru Nomura,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Takuya Kobayakawa,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Hikaru Takano,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Yuki Hirota,

    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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  • Dr. Tsutomu Murakami,

    1. AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640 (Japan)
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  • Prof. Naoki Yamamoto,

    1. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, 5 Science Drive 2, Singapore 117597 (Singapore)
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  • Prof. Hirokazu Tamamura

    Corresponding author
    1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
    • Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
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Abstract

Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1′-biphenyl]-4,4′-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity.

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