An Efficient Synthesis of Optically Active α-(<i>t</i>-Butoxycarbonylamino)-aldehydes from α-Amino Acids

Fehrentz, Jean‐Alain; Castro, Bertrand

doi:10.1055/s-1983-30471

Cited by 396 publications

(266 citation statements)

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“…Deacetylation generated the ~-cyclodextrin derivative mono-functionalized at the linear, fully flexible 4C-spacer as carboxylic acid. The tripeptide aldehyde HLeu-Leu-Nle-H was prepared as the semicarbazone according to known procedures [12][13][14][15] and was then linked to the cyclodextrin derivative via the PyBOP procedure [18]. Formation of intra-and/or intermolecular ester bonds with the free hydroxyl functions was not observed to occur under these conditions.…”

Section: Resultsmentioning

confidence: 99%

Cyclodextrins as templates for the presentation of protease inhibitors

Schaschke¹,

Hj²,

Assfalg-Machleidt³

et al. 1996

FEBS Letters

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Mono(6-succinylamido-6-deoxy)-13-cyclodextrin was synthesized by classical carbohydrate chemistry and used as a template mono-functionalized with the linear, fully flexible 4C-spacer carboxylate for covalent linkage of the calpain inhibitor leucyl-leucyl-norleucinal. Spectroscopic analyses of the conjugate do not support a self-inclusion of part of the hydrophobic peptide tail, but confirm its intra-or intermolecular interaction with the template moiety that leads to full water solubility. The inhibitory potency of the ~-cyclodextrin/peptide aldehyde construct was compared with that of the parent Ac-Leu-Leu-Nle-H against cathepsin B and calpain. Despite the large size of the template the inhibition of cathepsin B was only slightly reduced in full agreement with the X-ray structure of this enzyme which shows full accessibility of the S-subsites. For this enzyme the 4C-spacer is apparently sufficient to guarantee optimal interaction of the peptide tail with the binding cleft. Conversely, for gcalpain a significantly decreased inhibitory potency was obtained with the conjugate suggesting steric interference of the template in the binding process. These results show that the beneficial properties of the cyclodextrin template can be retained in conjugates with bioactive peptides if attention is paid to optimize in each case the size and nature of the spacer for optimal recognition of the grafted biomolecule.

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Section: Resultsmentioning

confidence: 99%

Cyclodextrins as templates for the presentation of protease inhibitors

Schaschke¹,

Hj²,

Assfalg-Machleidt³

et al. 1996

FEBS Letters

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“…After 16 h at room temperature, the resin was washed with DMF and deprotected with TFA (twice for 1 min). The reductive amination was performed by adding to the resin a solution of Boc-Ala-H (0.172 g, 1 mmol), synthesized by the method of Fehrenz and Castro [11], in dry THF (4 ml) together with acetic acid (40 µl) and sodium cyanoborohydride (93 mg, 1.5 mmol). This solution was shaken at room temperature for 30 min, after which a negative ninhydrin test showed the reaction to be complete.…”

Section: -(Boc-p-aminobenzoyl-ochmentioning

confidence: 99%

Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Shrimpton¹,

Abbenante

Lew³

et al. 2000

Biochemical Journal

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Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with α-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a Ki of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

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“…Последняя, в [17] ; b) LDA, MeCO [13] вовлечен в реакцию альдольной конденсации с этилацетатом. В результате получена смесь диастереомерных гидроксиэфиров 25 и 26, которую через окисление и стереоспецифическое восстановление превратили в необходимый диастереоизомер 26, а полученная из него кислота 27 конденсирована с производным цистеина 28 (Схема 6).…”

Section: Otbs Otbs Otbs Otbsunclassified