Synthesis of the peptidic α-hydroxy amides phebestin, probestin, and bestatin from α-keto amide precursors

Wasserman, Harry H.; Xia, Mingde; Petersen, Anders K.; Jorgensen, Matthew R.; Curtis, Erin A.

doi:10.1016/s0040-4039(99)01143-0

Cited by 39 publications

(26 citation statements)

References 22 publications

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“…As predicted, chelating reagents (Zn(BH 4 ) 2 ) and others that favor Felkin-Anh products (l-selectride, LiAlH(OtBu) 3 , NaBH 4 ) showed an accumulation of the syn product, whereas DIBAL-H gave a slightly increased amount of the anti product. Surprisingly, the high syn-selectivity previously reported for the use of Zn(BH 4 ) 2 in the reduction of a-keto amides [36] was not observed with aketo ester 5.…”

Section: Diastereoselective Reductionmentioning

confidence: 64%

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

et al. 2006

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A synthetic concept is presented that allows the construction of peptide isostere libraries through polymer-supported C-acylation reactions. A phosphorane linker reagent is used as a carbanion equivalent; by employing MSNT as a coupling reagent, the C-acylation can be conducted without racemization. Diastereoselective reduction was effected with L-selectride. The reagent linker allows the preparation of a norstatine library with full variation of the isosteric positions including the P1 side chain that addresses the protease S1 pocket. Therefore, the concept was employed to investigate the P1 site specificity of peptide isostere inhibitors systematically. The S1 pocket of several aspartic proteases including plasmepsin II and cathepsin D was modeled and docked with approximately 500 amino acid side chains. Inspired by this virtual screen, a P1 site mutation library was designed, synthesized, and screened against three aspartic proteases (plasmepsin II, HIV protease, and cathepsin D). The potency of norstatine inhibitors was found to depend strongly on the P1 substituent. Large, hydrophobic residues such as biphenyl, 4-bromophenyl, and 4-nitrophenyl enhanced the inhibitory activity (IC50) by up to 70-fold against plasmepsin II. In addition, P1 variation introduced significant selectivity, as up to 9-fold greater activity was found against plasmepsin II relative to human cathepsin D. The active P1 site residues did not fit into the crystal structure; however, molecular dynamics simulation suggested a possible alternative binding mode.

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Section: Diastereoselective Reductionmentioning

confidence: 64%

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

et al. 2006

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“…The key strategy for the synthesis of bestatin and its analogs is how to prepare the threo-β-amino-α-hydroxy acids moiety [14][15][16][17]. Recently, we have reported an efficient and stereoselective method for bestatin and its analog AHPBA-Val from chiral synthons, trans-oxazolidine methyl esters 2, which are properly protected forms of threo-β-amino-α-hydroxy acids (Figure 3) [18].…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Synthesis of Novel Bestatin Analogs

Seo¹,

Lee²,

Kim³

2015

Applied Chemistry for Engineering

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Two new analogs of bestatin were prepared from D-leucine and D-valine in a stereoselective and efficient way. An aminopeptidase inhibitor bestatin shows significant biological effects on immunomodulation and is marketed for the treatment of acute myelocytic leukemia. The key intermediates, trans-oxazolidine methyl esters 2a and 2b, were obtained with more than 20 to 1 stereoselectivity in a one-pot procedure by the three cascade reactions between N-hydroxymethyl protected α-amino aldehydes (4a and 4b) and phenylsulfonylnitromethane (PhSO2CH2NO2) and the following in-situ ozonolysis. Basic hydrolysis of 2a and 2b, and then the peptide coupling with L-Leu-OMe produced the protected derivatives of two new bestatin analogs, 3a and 3b, respectively. The new isobutyl and isopropyl analogs of bestatin (1a and 1b) were produced in overall 51% and 38% yields, respectively, with high stereoselectivity from the corresponding protected α-amino aldehydes 4 in a six-step process.

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“…MJ716-m3 [132]. Some stereoselective syntheses of phebestin have been reported [133][134][135]. Probestin, a tetrapeptide with the structure (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucyl-L-prolyl-L-proline, was extracted from Streptomyces azureus MH663-2F6 [136,137].…”

Section: Inhibitors Of Aminopeptidasesmentioning

confidence: 99%