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. 2018 Apr 24;3(4):4441-4452.
doi: 10.1021/acsomega.8b00354. eCollection 2018 Apr 30.

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ1-Pyrroline-5-carboxylate Reductase Inhibitors

Renzhe Qian  1 , Thomas Kalina  1 , Jeannie Horak  2 , Samuele Giberti  3 , Giuseppe Forlani  3 , Friedrich Hammerschmidt  1
Affiliations

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ1-Pyrroline-5-carboxylate Reductase Inhibitors

Renzhe Qian et al. ACS Omega. .

Abstract

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding (S)-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and N-hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and (R)-enantiomers (ee 92-99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ1-pyrroline-5-carboxylate synthetase, and δ1-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Phosphonic acid analogues of proline and proline analogues.
Scheme 1
Scheme 1. Preparation of (±)-, (R)-, and (S)-Proline [(±)-, (R)-, and (S)-1]
Scheme 2
Scheme 2. Preparation of (±)- and (R)-Isoxazolidin-3-ylphosphonic Acid [(±)- and (R)-2]
Nos = 4-nitrobenzenesulfonyl; DIAD = diisopropyl azodicarboxylate, PhthNOH = N-hydroxyphthalimide.
Scheme 3
Scheme 3. Preparation of (±)- and (R)-(−)-1,2-Oxazinan-3-ylphosphonic Acid [(±)- and (R)-6]
Nos = 4-nitrobenzenesulfonyl; DIAD = diisopropyl azodicarboxylate, PhthNOH = N-hydroxyphthalimide.
Scheme 4
Scheme 4. Preparation of (±)- and (R)-(+)-Isoxazolidin-5-ylphosphonic Acid [(±)- and (R)-3]
DIAD = diisopropyl azodicarboxylate, PhthNOH = N-hydroxyphthalimide.
Scheme 5
Scheme 5. Attempted Preparation of Protected (±)-Pyrazolidin-3-ylphosphonic Acid [(±)-27]
Scheme 6
Scheme 6. Preparation of (±)-Pyrazolidin-3-ylphosphonic Acid [(±)-4]
Nos = 4-nitrobenzenesulfonyl, Tf = trifluoromethanesulfonyl, Ms = methanesulfonyl.
Scheme 7
Scheme 7. Preparation of (R)-Pyrazolidin-3-ylphosphonic Acid [(R)-4]
Nos = 4-nitrobenzenesulfonyl.
Figure 2
Figure 2
Effect of millimolar concentrations of compounds (R)-, (S)-1, and (R)-6 on the activity of A. thaliana P5C reductase. The inhibition brought about by the physiological product of the enzyme, proline, is also shown as a term of comparison.
See this image and copyright information in PMC

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