Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres

Tetsuo Narumi; Ryoko Hayashi; Kenji Tomita; Kazuya Kobayashi; Noriko Tanahara; Hiroaki Ohno; Takeshi Naito; Eiichi Kodama; Masao Matsuoka; Shinya Oishi; Nobutaka Fujii

doi:10.1039/B917236J

Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres†

Tetsuo Narumi,^ab Ryoko Hayashi,^a Kenji Tomita,^a Kazuya Kobayashi,^a Noriko Tanahara,^a Hiroaki Ohno,^a Takeshi Naito,^a Eiichi Kodama,^c Masao Matsuoka,^c Shinya Oishi*^a and Nobutaka Fujii*^a

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* Corresponding authors

^a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
E-mail: soishi@pharm.kyoto-u.ac.jp, nfujii@pharm.kyoto-u.ac.jp
Fax: +81-75-753-4570
Tel: +81-75-753-4551

^b Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan

^c Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Abstract

A set of cyclic peptide analogues of a selective CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)] were synthesized and bioevaluated. Using (E)-alkene and (Z)-fluoroalkene dipeptide isosteres for Arg-Arg and Arg-Nal substructures, indispensable or the partial contribution of the two peptide bonds to the CXCR4 antagonism and anti-HIV activity was demonstrated. FC131 and the analogues were shown to selectively inhibit SDF-1 binding to CXCR4, whereas no inhibition of binding of SDF-1 to CXCR7 was observed.

Organic & Biomolecular Chemistry

Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres†

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Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres

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