Z-D-glutamic acid γ-tert-butyl ester
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Z-D-glutamic acid γ-tert-butyl ester

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Category
CBZ-Amino Acids
Catalog number
BAT-003289
CAS number
51644-83-8
Molecular Formula
C17H23NO6
Molecular Weight
337.40
Z-D-glutamic acid γ-tert-butyl ester
IUPAC Name
(2R)-5-[(2-methylpropan-2-yl)oxy]-5-oxo-2-(phenylmethoxycarbonylamino)pentanoic acid
Synonyms
Z-D-Glu(OtBu)-OH; Z-D-glutamic acid-5-tert-butyl ester
Appearance
White powder
Purity
≥ 98% (HPLC)
Density
1.197 g/cm3
Melting Point
80-90 °C
Boiling Point
522.6°C
Storage
Store at 2-8 °C
InChI
InChI=1S/C17H23NO6/c1-17(2,3)24-14(19)10-9-13(15(20)21)18-16(22)23-11-12-7-5-4-6-8-12/h4-8,13H,9-11H2,1-3H3,(H,18,22)(H,20,21)/t13-/m1/s1
InChI Key
GLMODRZPPBZPPB-CYBMUJFWSA-N
Canonical SMILES
CC(C)(C)OC(=O)CCC(C(=O)O)NC(=O)OCC1=CC=CC=C1

Z-D-glutamic acid γ-tert-butyl ester is a derivative of D-glutamic acid, where the amino group is protected by a benzyloxycarbonyl (Z) group, and the γ-carboxyl group is esterified with a tert-butyl group. This compound is commonly used in peptide synthesis and other chemical processes, offering the benefit of protecting functional groups that could otherwise react undesirably. The Z group offers stability for the amino functionality, while the γ-tert-butyl ester protects the γ-carboxyl group, enabling selective deprotection in synthetic applications.

One primary application of Z-D-glutamic acid γ-tert-butyl ester is in solid-phase peptide synthesis (SPPS). The Z group protects the amino group, allowing for controlled peptide elongation during synthesis. The γ-tert-butyl ester ensures that the side-chain carboxyl group remains stable, preventing unwanted reactions during the peptide formation process. This makes it a valuable intermediate for producing peptides that contain glutamic acid residues, which are commonly found in bioactive peptides and proteins.

In pharmaceutical development, Z-D-glutamic acid γ-tert-butyl ester is utilized in the synthesis of glutamate analogs and derivatives. These compounds play an important role in modulating the glutamate system, which is involved in numerous neurological processes. By incorporating Z-D-glutamic acid γ-tert-butyl ester into glutamate-based molecules, researchers can create targeted therapies for conditions such as Alzheimer’s disease, epilepsy, and other neurological disorders where glutamate signaling is disrupted.

Z-D-glutamic acid γ-tert-butyl ester is also important in the design of peptidomimetics. Its stable protective groups facilitate the incorporation of the glutamic acid derivative into non-peptide molecules that mimic natural peptides. These peptidomimetics can be engineered to have improved stability and resistance to enzymatic degradation, making them potential candidates for drug development. By mimicking the structure of natural peptides, these compounds can act on specific biological targets with greater efficacy and stability.

Additionally, this compound plays a crucial role in bioconjugation applications, such as in the development of antibody-drug conjugates (ADCs). The selective protection and deprotection of the functional groups in Z-D-glutamic acid γ-tert-butyl ester allow for the conjugation of therapeutic agents or targeting ligands, facilitating targeted drug delivery to specific cells or tissues. This capability is especially useful in cancer therapies, where ADCs can deliver drugs directly to tumor cells, minimizing off-target effects and maximizing treatment efficacy.

1. Methotrexate analogues. 31. Meta and ortho isomers of aminopterin, compounds with a double bond in the side chain, and a novel analogue modified at the alpha-carbon: chemical and in vitro biological studies
A Rosowsky, H Bader, R A Forsch, R G Moran, J H Freisheim J Med Chem. 1988 Apr;31(4):763-8. doi: 10.1021/jm00399a013.
Five heretofore undescribed analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized and tested as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. The meta isomer of AMT was obtained from 2,4-diamino-6-(bromomethyl)pteridine and m-(aminobenzoyl)-L-glutamic acid, while the ortho isomer was obtained via the same route by using alpha-methyl gamma-tert-butyl o-(aminobenzoyl)-L-glutamate instead of the free acid. Analogues of MTX and AMT containing a double bond in the side chain were prepared from dimethyl D,L-2-amino-4-hexenedioate and 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively. Finally, a positional isomer of MTX with the CH2CH2COOH moiety moved from the alpha-carbon to the adjacent carboxamide nitrogen was synthesized from 3-[N-(carboxymethyl)amino]propanoic acid diethyl ester and 4-amino-4-deoxy-N10-methylpteroic acid. The positional isomers of AMT were weak DHFR inhibitors and showed very little growth-inhibitory activity against L1210 murine leukemia cells or the MTX-resistant L1210/R81 mutant line in culture. The MTX and AMT analogues with the CH2CH2COOH moiety replaced by a CH2CH = CHCOOH side chain showed anti-DHFR activity similar to that of the previously described saturated compound N-(4-amino-4-deoxy-N10-methylpteroyl)-L-2-aminoadipic acid, but were less potent than the parent drugs. The MTX analogue with the CH2CH2COOH side chain displaced from C to N was weakly bound to DHFR, confirming the importance of an intact CONH moiety, and showed greatly diminished cell growth inhibitory potency relative to MTX. None of the compounds was a substrate for folylpolyglutamate synthetase (FPGS) from mouse liver. Furthermore, inhibition of folic acid polyglutamylation in vitro at equimolar 500 microM concentrations of drug and substrate was negligible. The structural changes embodied in these five novel compounds are therefore too great for binding to the FPGS active site.
2. Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-γ-carboxyglutamic acid
Daniel J Smith, Glenn P A Yap, James A Kelley, Joel P Schneider J Org Chem. 2011 Mar 18;76(6):1513-20. doi: 10.1021/jo101940k. Epub 2011 Feb 3.
L-γ-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-α-Fmoc-L-γ-carboxyglutamic acid γ,γ'-tert-butyl ester (Fmoc-Gla(O(t)Bu)(2)-OH), a suitably protected analogue for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structure-based design was inspired by the blue copper protein rusticyanin. The five-coordinate complex is formed by Shiff base formation between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl)aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the α-carbon of the glycine portion of the complex occurs in a diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex, the asymmetric synthesis of Fmoc-Gla(O(t)Bu)(2)-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield.
3. Discovery of new targeting agents against GAPDH receptor for antituberculosis drug delivery
Muhammad Amirul Asyraf Noh, Siti Sarah Fazalul Rahiman, Habibah A Wahab, Amirah Mohd Gazzali J Basic Clin Physiol Pharmacol. 2021 Jun 25;32(4):715-722. doi: 10.1515/jbcpp-2020-0435.
Objectives: Tuberculosis (TB) remains a public health concern due to the emergence and evolution of multidrug-resistant strains. To overcome this issue, reinforcing the effectiveness of first line antituberculosis agents using targeted drug delivery approach is an option. Glyceraldehyde-3-Phosphate Dehydrogenase (GADPH), a common virulence factor found in the pathogenic microorganisms has recently been discovered on the cell-surface of Mycobacterium tuberculosis, allowing it to be used as a drug target for TB. This study aims to discover active small molecule(s) that target GAPDH and eventually enhance the delivery of antituberculosis drugs. Methods: Ten ligands with reported in vitro and/or in vivo activities against GAPDH were evaluated for their binding interactions through molecular docking studies using AutoDock 4.2 program. The ligand with the best binding energy was then modified to produce 10 derivatives, which were redocked against GAPDH using previous protocols. BIOVIA Discovery Studio Visualizer 2019 was used to explore the ligand-receptor interactions between the derivatives and GAPDH. Results: Among the 10 ligands, curcumin, koningic acid and folic acid showed the best binding energies. Further analysis on the docking of two folic acid derivatives, F7 (γ-{[tert-butyl-N-(6-aminohexyl)]carbamate}folic acid) and F8 (folic acid N-hydroxysuccinimide ester) showed that the addition of a bulky substituent at the carboxyl group of the glutamic acid subcomponent resulted in improved binding energy. Conclusions: Folic acid and the two derivatives F7 and F8 have huge potentials to be developed as targeting agents against the GAPDH receptor. Further study is currently on-going to evaluate the effectiveness of these molecules in vitro.
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