Prodrug Forms of <i>N</i>-[(4-Deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)]-glutarate, a Potent Inhibitor of Folylpoly-γ-glutamate Synthetase: Synthesis and Hydrolytic Stability

Feng, Yue; Coward, James K.

doi:10.1021/jm050871p

Cited by 55 publications

(46 citation statements)

References 69 publications

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“…First, the free radical hydrophosphination of vinyl glycine 131 [118], followed by the addition to an electro-deficient olefin 132 [119] and the methylation with trimethylsilyldiazomethane afforded phosphinate ester 133. Thereafter, the cleavage of the benzyl group followed by acetylation and amide coupling or esterification gave amide 134 or methyl ester 135.…”

Section: Inhibitors Of Tubulin Polyglutamylationmentioning

confidence: 99%

Synthesis and Biological Applications of Phosphinates and Derivatives

Virieux

Volle

Bakalara

et al. 2014

Topics in Current Chemistry

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This review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also described.

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Section: Inhibitors Of Tubulin Polyglutamylationmentioning

confidence: 99%

Synthesis and Biological Applications of Phosphinates and Derivatives

Virieux

Volle

Bakalara

et al. 2014

Topics in Current Chemistry

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“…Following a known protocol, we started our synthesis with enantiomerically pure Cbz-(S)-vinylglycine (3), which is readily available by a two-step synthesis from Cbz-(S)-methionine (2). 23 In parallel, dibenzyl glutarate (5) was prepared from benzyl acrylate (4) via a Baylis-Hilman type reaction with (n-Bu) 3 P. 24 Addition of ammonium hypophosphite gave phosphinic acid 6 as a racemate. Following a protocol of Vitharana et al, 25 stepwise crystallization with first yohimbine and second (S)-methylbenzylamine gave (S)-6 and (R)-6 in 31 and 28% yield, respectively over two steps.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of dipeptide mimics based on amino phosphinate backbones and cyclic derivatives

Rüping¹,

Küchenthal²,

Maison³

2015

Arkivoc

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Dialkyl phosphinates are valuable peptide mimics for metallopeptidase targets. Despite their large pharmaceutical potential, the synthesis of many phosphinates remains challenging. An additional drawback for many applications is the high polarity of the phosphinate group. Herein we describe the synthesis of stereoisomerically pure GPI (1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA (prostate specific membrane antigen). In addition, analogous cyclic phosphinate esters 13, 16 and 23 are reported that might be useful as less polar ligands for metallo peptidase binding. The key step to these new 1,2-oxaphosphorinan-2-ones is an intramolecular cyclization of an intermediate H-phosphinate. The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2-and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds.

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“…The first is to synthesize prodrugs that will allow these hydrophilic moieties to enter cells for subsequent activation. An initial attempt in this regard utilized readily hydrolyzable pivaloyloxymethyl (POM) esters that have been used previously to deliver several hydrophilic drugs [31]. Unfortunately, previously unrecognized relatively rapid (t 0.5 = 30 min) hydrolysis of the esters in medium or solvent was documented.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of human folylpolyglutamate synthetase by diastereomeric phosphinic acid mimics of the tetrahedral intermediate

McGuire

Bartley

Tomsho

et al. 2009

Archives of Biochemistry and Biophysics

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Phosphorus-containing pseudopeptides, racemic at the C-terminal α-carbon, are potent mechanismbased inhibitors of folylpolyglutamate synthetase (FPGS). They are mimics of the tetrahedral intermediate postulated to form during FPGS-catalyzed biosynthesis of poly(γ-L-glutamates). In the present paper, the FPGS inhibitory activity of each diastereomer coupled to three heterocycles is reported. The high R f pseudopeptide containing the 5,10-dideazatetrahydropteroyl (DDAH 4 Pte) heterocycle is most potent (K is = 1.7 nM). While the heterocyclic portion affects absolute FPGS inhibitory potency, the high R f species is more potent in each pair containing the same heterocycle. This species presumably has the same stereochemistry as the natural folate polyglutamate, i.e., (LGlu-γ-L-Glu). Unexpectedly, the low R f (presumed L-Glu-γ-D-Glu) species are only slightly less potent (<30-fold) less potent than their diastereomers. Further study of this phenomenon comparing L-Glu-γ-L-Glu and L-Glu-γ-D-Glu dipeptide-containing FPGS substrates shows that <1% contamination of commercial D-Glu precursors by L-Glu may give misleading information if L-Glu-γ-L-Glu substrates have low K m values.

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Prodrug Forms of N-[(4-Deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)]-glutarate, a Potent Inhibitor of Folylpoly-γ-glutamate Synthetase: Synthesis and Hydrolytic Stability

Cited by 55 publications

References 69 publications

Synthesis and Biological Applications of Phosphinates and Derivatives

Synthesis and Biological Applications of Phosphinates and Derivatives

Synthesis of dipeptide mimics based on amino phosphinate backbones and cyclic derivatives

Inhibition of human folylpolyglutamate synthetase by diastereomeric phosphinic acid mimics of the tetrahedral intermediate

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