SN2'-Reactions of Peptide Aziridines. A Cuprate-Based Approach to (E)-Alkene Isosteres

Wipf, Peter; Fritch, Paul C.

doi:10.1021/jo00096a033

Cited by 145 publications

(47 citation statements)

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“…The practical utility of (E)-alkene dipeptide isosteres (EADIs) and reduced amide-type dipeptide isosteres (RADIs) has been intensively investigated in their introduction into biologically active peptides (Fig. (2)) [14,25,34,38,82,86,100]. Backbone replacements of amide bonds in peptides by EADIs and RADIs provide information on the contributions of the corresponding amide bonds to biological activity toward development of peptide-lead drugs.…”

Section: -2 Low Molecular Weight Cxcr4 Antagonists Based On Cyclic mentioning

confidence: 99%

Development of Anti-HIV Agents Targeting Dynamic Supramolecular Mechanism: Entry and Fusion Inhibitors Based on CXCR4/CCR5 Antagonists and gp41-C34-Remodeling Peptides

Tamamura¹,

Otaka²,

Fujii

2005

CHR

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A molecular mechanism involved both in HIV-entry and -fusion steps has been disclosed in detail: The interaction of an HIV envelope protein, gp120, with chemokine receptors, CXCR4 and CCR5, which were identified as major co-receptors in association with CD4, triggers conformational changes in the gp120-gp41 (another envelope protein) complex, and subsequently forms the trimer-of-hairpins structure of gp41 followed by virus-cell membrane fusion. The elucidation of the above dynamic supramolecular mechanism in HIV-entry and -fusion has provided insights into new type of drugs that can block HIV infection. Based on this, we have developed not only coreceptor antagonists (1) but also fusion inhibitors (2). (1) Potent CXCR4 antagonists, T22 and T140, have been developed through the structure-activity relationship studies on tachyplesins and polyphemusins that are horseshoe crabs' antimicrobial peptides. T22, which was initially found to bind gp120 and CD4, and T140 selectively suppress T-cell line-tropic HIV-1 (X4-HIV-1) entry based on their specific binding to CXCR4. Furthermore, molecular-size reduction of T140 using cyclic pentapeptide templates brought us to find low molecular weight CXCR4 antagonists, such as FC131. (2) Artificial remodeling of a gp41 fragment, C34, has led to development of strong inhibitors of HIV-fusion into cells. These fusion inhibitors effectively block the formation of the trimer-of-hairpins structure of gp41. HIV-entry/fusion inhibitors such as CXCR4 antagonists and C34 analogs would improve the clinical chemotherapy of AIDS and HIV-infected patients. This review article focuses on our recent research on the development of the above two types of inhibitors, including comparative studies with several CXCR4 antagonists besides T22/T140-related compounds and other fusion inhibitors such as Fuzeon (T-20).

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Section: -2 Low Molecular Weight Cxcr4 Antagonists Based On Cyclic mentioning

confidence: 99%

Development of Anti-HIV Agents Targeting Dynamic Supramolecular Mechanism: Entry and Fusion Inhibitors Based on CXCR4/CCR5 Antagonists and gp41-C34-Remodeling Peptides

Tamamura¹,

Otaka²,

Fujii

2005

CHR

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“…= 5:1). (2-Carboxyvinyl)aziridines are particularly useful reagents due, amongst other properties, to their facile conversion into a range of peptidomimetic candidates [41][42][43][44]. In an attempt to use our method to deliver these trifunctional aziridines, we reacted the lithium anion derived from methyl (E)-3-bromocrotonate with N-diphenylphosphinylbenzaldimine.…”

Section: Synthesis Of N-dpp Vinyl Aziridines Initial Studiesmentioning

confidence: 99%

“…At the time, these data represented the first examples of a 100% regioselective ring opening of simple vinyl aziridines by using lowerorder organocuprates. Previously, only 2-(2-carboxyethenyl)-aziridines had been shown to undergo ring-opening reactions with a range of nucleophiles [41]. The π-allyl complexes derived from aziridines 1 and 2, formed in situ by using substoichiometric Pd(PPh 3 ) 4 , underwent successful reaction with sodiomalonate and sodium bisphenylsulfonylmethide, again with complete regiocontrol via an S N 2′-like reaction to give ring-opened products in acceptable yield (Table 2, entries 7, 8, 11, 12).…”

Section: Ring Opening Of N-dpp Vinyl Aziridinesmentioning

confidence: 99%

Preparation and Ring-Opening Reactions of N-Diphenylphosphinyl Vinyl Aziridines

Cantrill¹,

Jarvis²,

Osborn³

et al. 1996

Synlett

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“…[1][2][3][4][5][6][7] Backbone replacements of amide bonds in peptides by EADIs provide information on the contributions of the corresponding amide bonds on biological activity. We previously established a completely stereocontrolled synthetic process for L,L-type and L,D-type EADIs starting from L-amino acid.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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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.

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SN2'-Reactions of Peptide Aziridines. A Cuprate-Based Approach to (E)-Alkene Isosteres

Cited by 145 publications

References 1 publication

Development of Anti-HIV Agents Targeting Dynamic Supramolecular Mechanism: Entry and Fusion Inhibitors Based on CXCR4/CCR5 Antagonists and gp41-C34-Remodeling Peptides

Development of Anti-HIV Agents Targeting Dynamic Supramolecular Mechanism: Entry and Fusion Inhibitors Based on CXCR4/CCR5 Antagonists and gp41-C34-Remodeling Peptides

Preparation and Ring-Opening Reactions of N-Diphenylphosphinyl Vinyl Aziridines

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

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