Stereoselective synthesis of [L-Arg-L/D-3-(2-naphthyl)alanine]-type (E)-alkene dipeptide isosteres and its application to the synthesis and biological evaluation of pseudopeptide analogues of the CXCR4 antagonist FC131.
L,L-Type and L,D-type (E)-alkene dipeptide isosteres (EADIs) that have unnatural side chains at the alpha-position were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc-copper-mediated anti-S(N)2' reactions toward a single substrate of gamma,delta-cis-gamma,delta-epimino (E)-alpha,beta-enoate. The utility of this methodology was demonstrated by the stereoselective synthesis of a set of diastereomeric EADIs of L-Arg-L/D-3-(2-naphthyl)alanine (Nal) that is contained in a small CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)]. Furthermore, a (Nal-Gly)-type EADI was synthesized by samarium diiodide (SmI(2))-induced reduction of a gamma-acetoxy-alpha,beta-enoate. Several FC131 analogues, in which these EADIs were inserted for reduction of their peptide character, were synthesized with analogues containing reduced amide-type dipeptide isosteres to investigate the importance of these amide bonds for anti-HIV and CXCR4-antagonistic activity.
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
Hiramatsu
Kenichi
K
Ueda
Satoshi
S
Wang
Zixuan
Z
Kusano
Shuichi
S
Terakubo
Shigemi
S
Trent
John O
JO
Peiper
Stephen C
SC
Yamamoto
Naoki
N
Nakashima
Hideki
H
Otaka
Akira
A
Fujii
Nobutaka
N
D000409:Alanine / Q000737:chemistry*; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004151:Dipeptides / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D004151:Dipeptides; D009281:Naphthalenes; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; C496951:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl); D000409:Alanine