Practical, Stereoselective Synthesis of Palinavir, a Potent HIV Protease Inhibitor

Beaulieu, Pierre L.; Lavallée, Pierre; Abraham, Abraham; Anderson, Paul C.; Boucher, Colette; Bousquet, Yves; Duceppe, Jean‐Simon; Gillard, James; Gorys, Vida; Grand‐Maître, Chantal; Grenier, Louis; Guindon, Yvan; Guse, Ingrid; Plamondon, Louis; Soucy, François; Valois, Serge; Wernic, and Dominik; Yoakim, Christiane

doi:10.1021/jo9702655

Cited by 74 publications

(39 citation statements)

References 44 publications

(35 reference statements)

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“…For example, cis-4-L-HyPip is a component of palinavir, an HIV protease inhibitor (11,12), and cis-5-hydroxy-L-pipecolic acid (cis-5-L-HyPip) is a precursor for the synthesis of the ␤-lactamase inhibitor MK-7655 (13). Thus, the development of processes for the industrial synthesis of HyPips may be of great significance.…”

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confidence: 99%

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Hibi

Mori

Miyake

et al. 2016

Appl Environ Microbiol

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Hydroxypipecolic acids are bioactive compounds widely distributed in nature and are valuable building blocks for the organic synthesis of pharmaceuticals. We have found a novel hydroxylating enzyme with activity toward L-pipecolic acid (L-Pip) in a filamentous fungus, Fusarium oxysporum c8D. The enzyme L-Pip trans-4-hydroxylase (Pip4H) of F. oxysporum (FoPip4H) belongs to the Fe(II)/␣-ketoglutarate-dependent dioxygenase superfamily, catalyzes the regio-and stereoselective hydroxylation of L-Pip, and produces optically pure trans-4-hydroxy-L-pipecolic acid (trans-4-L-HyPip). Amino acid sequence analysis revealed several fungal enzymes homologous with FoPip4H, and five of these also had L-Pip trans-4-hydroxylation activity. In particular, the homologous Pip4H enzyme derived from Aspergillus nidulans FGSC A4 (AnPip4H) had a broader substrate specificity spectrum than other homologues and reacted with the L and D forms of various cyclic and aliphatic amino acids. Using FoPip4H as a biocatalyst, a system for the preparative-scale production of chiral trans-4-L-HyPip was successfully developed. Thus, we report a fungal family of L-Pip hydroxylases and the enzymatic preparation of trans-4-L-HyPip, a bioactive compound and a constituent of secondary metabolites with useful physiological activities.H ydroxypipecolic acids (HyPips) are naturally occurring sixmembered heterocyclic hydroxy amino acids that are widely distributed in nature. For instance, 4-hydroxy-, 5-hydroxy-, and 4,5-dihydroxypipecolic acids have been found in various members of the plant family (1-4). Likewise, 5-hydroxypipecolic acid was found to be present in mammalian brain and blood (5). HyPips are also components of some peptide antibiotics, terpenoids, and alkaloids, for example, Thus, the enzymatic hydroxylation of L-Pip was achieved as a side reaction of L-proline hydroxylase. To date, specific L-Piphydroxylating enzymes have not been reported, despite the fact that HyPips are important metabolites found in plants and mammals. In the present study, we identified and characterized L-Pip hydroxylases broadly conserved in some filamentous fungi. We found that the newly discovered L-Pip hydroxylases were particularly suitable biocatalysts for the asymmetric hydroxylation of cyclic amino acids, such as pipecolic acids and prolines. Moreover, the widespread distribution of genes encoding L-Pip hydroxylases indicates some important physiological roles of fungal secondary metabolites related to trans-4-L-HyPip. MATERIALS AND METHODSStrains and culture. Microorganisms isolated from soil and plant samples were cultured in GP medium comprised of 0.15% (wt/vol) KH 2 PO 4 , 0.05% (wt/vol) K 2 HPO 4 , 0.1% (wt/vol) NH 4 Cl, 0.03% (wt/vol) MgSO 4 ·7H 2 O, 0.01% (wt/vol) yeast extract, 0.025% (wt/vol) glucose, and 0.1% (wt/vol) L-Pip (pH 7.0) and grown at 28°C with shaking. Escherichia coli JM109 and Rosetta2(DE3) (Novagen, WI, USA) were used as host strains for the overexpression of the recombinant enzymes and cultured at 28°C in LB medium, comprised of 1% (wt/v...

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confidence: 99%

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Hibi

Mori

Miyake

et al. 2016

Appl Environ Microbiol

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“…Compound 4 lacking aminoacids Val and Met from the peptide sequence resulted more soluble, but devoid of enzyme inhibitory activity. basic alumina [14], followed by HATU mediated coupling with dipeptide BocMetValOH gave compound 14.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of BACE-1 by Hydroxyethylsulfide, Hydroxyethylamine and Hydroxyethylurea Isosteric Replacements

Romeo¹

2005

LDDD

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New inhibitors of the ß-site amyloid precursor protein cleaving enzyme (BACE-1) are described. The hydroxyethyl transition state isostere of GT1017 has been replaced by the hydroxyethylamine (HEA), the hydroxyethylsulfide or the hydroxyethylurea groups. Biological evaluation has shown that the HEA analogue, obtained as epimeric mixture, inhibited BACE-1 with an IC 50 =0.12µM. Stereoselective synthesis showed surprisingly that the most active stereoisomer was the (R)-HEA transition state analogue with an IC 50 =0.014µM.

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“…N-Boc-(2S,4R)-4-hydroxypipecolic tert-butylamide (36) 21,25 was first converted to the (2S,4S)-4-iodo or 4-bromo derivatives (37) via mesylation and displacement with inversion using iodide or bromide. Intermediate 37 was then treated with sulfur nucleophiles to deliver the desired (2S,4R)-4-substituted pipecolic amide derivatives 38a-c through an overall double-inversion process.…”

Section: Resultsmentioning

confidence: 99%

“…After the solution was dried over MgSO4, evaporation of the solvent gave an oil that was purified by flash chromatography using 5% EtOH in CHCl3 as eluent. Preparation of (2S,4R)-4-bromopipecolic tert-butylamide 37 (X ) Br): (2S,4R)-4-hydroxypipecolic tert-butylamide 36 21,25 (70.10 g, 0.233 mol) was dissolved in dry THF (700 mL), and Et3N (42 mL, 0.30 mol) was added. The solution was cooled in an ice-water bath under a nitrogen atmosphere, and methanesulfonyl chloride (22.5 mL, 0.29 mol) was added dropwise over 30 min.…”

Section: Methodsmentioning

confidence: 99%

2‘,6‘-Dimethylphenoxyacetyl: A New Achiral High Affinity P₃-P₂Ligand for Peptidomimetic-Based HIV Protease Inhibitors

Beaulieu¹,

Anderson²,

Cameron³

et al. 2000

J. Med. Chem.

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Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P(3)-P(2) quinaldic-valine portion of 1 was replaced by 2', 6'-dimethylphenoxyacetyl. With EC(50)'s in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P(3)-P(2) position of hydroxyethylamine-based HIV protease inhibitors.

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Practical, Stereoselective Synthesis of Palinavir, a Potent HIV Protease Inhibitor

Cited by 74 publications

References 44 publications

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Inhibition of BACE-1 by Hydroxyethylsulfide, Hydroxyethylamine and Hydroxyethylurea Isosteric Replacements

2‘,6‘-Dimethylphenoxyacetyl: A New Achiral High Affinity P₃-P₂Ligand for Peptidomimetic-Based HIV Protease Inhibitors

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Practical, Stereoselective Synthesis of Palinavir, a Potent HIV Protease Inhibitor

Cited by 74 publications

References 44 publications

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Inhibition of BACE-1 by Hydroxyethylsulfide, Hydroxyethylamine and Hydroxyethylurea Isosteric Replacements

2‘,6‘-Dimethylphenoxyacetyl: A New Achiral High Affinity P3-P2Ligand for Peptidomimetic-Based HIV Protease Inhibitors

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2‘,6‘-Dimethylphenoxyacetyl: A New Achiral High Affinity P₃-P₂Ligand for Peptidomimetic-Based HIV Protease Inhibitors