Enantioretentive alkylation of acyclic amino acids

Karady, Sandor; Amto, Joseph S.; Weinstock, Leonard M.

doi:10.1016/s0040-4039(01)81432-5

Cited by 117 publications

(32 citation statements)

References 8 publications

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“…40, 41 After screening the base, electrophile species, reagent ratio, reaction temperature and solvent, the best yield was obtained by using LiHMDS (2 equivalent) as the base, alkenyl iodide as the electrophile and anhydrous THF/HMPA (4:1, v/v) as the solvents at the temperature of -78°C. It is noteworthy that the addition sequence of the reagents greatly impacted the alkylation yield.…”

Section: Resultsmentioning

confidence: 99%

Design of Cell-Permeable Stapled Peptides as HIV-1 Integrase Inhibitors

et al. 2013

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HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with host proteins. We have previously identified peptide IN inhibitors derived from the alpha-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon-stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead compounds of novel HIV-1 IN inhibitors but also prototypical biochemical probes or ‘nanoneedles’ for the elucidation of HIV-1 IN dimerization and host co-factor interactions within their native cellular environment.

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Section: Resultsmentioning

confidence: 99%

Design of Cell-Permeable Stapled Peptides as HIV-1 Integrase Inhibitors

et al. 2013

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“…These include Schçllkopf's bis-lactim ether strategy, [41,42] Williams' diphenyloxazinones method, [43] and Seebach's oxazolidinone-based methodology, [44] or one of its variants. [45][46][47][48][49][50] By using an optimized Schçllkopf protocol, as described by Vassiliou et al, [51] (S)-a-Me-o-CN-Phe·HCl (12) was synthesized with good enantioselectivity (Scheme 1).…”

Section: Synthesismentioning

confidence: 99%

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

et al. 2011

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Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized β-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' β-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.

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“…To construct the requisite amino acid ester building blocks, we adopted a modification of the Seebach12/Karady13 chemistry for the self-regeneration of stereogenic centers (Scheme 2A), initially exploiting a tert -butyl carbamate (Boc) protecting group for the amines and an olefin (i.e., prenyl group) for the masked aldehydes (cf. 12 ).…”

Section: Construction Of 35-linked Polypyrrolinonesmentioning

confidence: 99%

Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

2010

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Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith–Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold. We developed effective synthetic protocols, both in solution and on solid supports, for iterative construction of diverse polypyrrolinones that present functionalized peptide-like side-chains. As a result of the rigid nature of the pyrrolinone scaffold, control over the backbone conformation could be exerted by modulation of the stereogenicity of the constituent monomers and the network of intramolecular hydrogen bonding. The extended conformation of the homochiral 3,5-linked polypyrrolinone scaffold proved to be an excellent mimic for β-strands and β-sheets. Application to enzyme inhibitor design and synthesis led not only to modest inhibitors of the aspartic acid protease renin and the matrix metalloprotease class of enzymes, but importantly to bioavailable HIV-1 protease inhibitors with subnanomolar binding constants. The design and synthesis of a competent peptide–pyrrolinone hybrid ligand for the class II major histocompatibility complex (MHC) antigen protein HLA-DR1 further demonstrated the utility of the 3,5-polypyrrolinone motif as a mimic for the extended polyproline type II peptide backbone. Equally important, we sought to define, by synthesis, the additional conformational space accessible to the polypyrrolinone structural motif, with the ultimate goal of accessing pyrrolinone-based turn and helix mimetics. Towards this end, a mono-N-methylated bispyrrolinone was found to adopt an extended helical array in the solid state. Subsequent synthesis of d,l-alternating (heterochiral) tetrapyrrolinones both validated the expected turn conformations in solution and led to a functionally active mimetic of a peptidal β-turn (similar to somatostatin). Finally, the design, synthesis, and structural evaluation of both acyclic and cyclic heterochiral (that is, d,l-alternating) hexapyrrolinones yielded nanotube-like assemblies in the solid state. Taken together, these results illustrate the remarkable potential of the 3,5-linked polypyrrolinone scaffold as β-strand, β-sheet, β-turn, and potentially helical peptidomimetics.

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Enantioretentive alkylation of acyclic amino acids

Cited by 117 publications

References 8 publications

Design of Cell-Permeable Stapled Peptides as HIV-1 Integrase Inhibitors

Design of Cell-Permeable Stapled Peptides as HIV-1 Integrase Inhibitors

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

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