Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres.
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.
Narumi
Tetsuo
T
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Hayashi
Ryoko
R
Tomita
Kenji
K
Kobayashi
Kazuya
K
Tanahara
Noriko
N
Ohno
Hiroaki
H
Naito
Takeshi
T
Kodama
Eiichi
E
Matsuoka
Masao
M
Oishi
Shinya
S
Fujii
Nobutaka
N
D000475:Alkenes / Q000737:chemistry*; D000595:Amino Acid Sequence; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry*; D006678:HIV / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D020128:Inhibitory Concentration 50; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D013237:Stereoisomerism
D000475:Alkenes; D004151:Dipeptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4