Hydroxyethylamine Dipeptide Isosteres Research Articles

Evaluating a Retro-Inverso Type Inhibitor of HTLV-1 Protease as a Competitive Inhibitor.

The inhibition mode of a retro-inverso (RI) inhibitor containing a hydroxyethylamine dipeptide isostere against the human T-cell leukemia virus type-1 (HTLV-1) protease was examined. Enzymatic evaluation of the RI-modified inhibitor containing a D-allo-Ile residue revealed that HTLV-1 was competitively inhibited. IC50 values of the RI-modified inhibitor and pepstatin A, a standard inhibitor of aspartic proteases, were nearly equivalent.

The Effects of Side-Chain Configurations of a Retro-Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease.

In this study, the effects of side-chain configurations of D-Ile residues of a retro–inverso (RI)-type inhibitor on the human T-cell leukemia virus type 1 (HTLV-1) protease containing a hydroxyethylamine dipeptide isostere were clarified. Prior to evaluation using the RI-type inhibitor, the effects of side-chain configurations of Ile residues of the substrate peptide on the HTLV-1 protease were examined to estimate the influence of side-chain configurations on enzyme activity. Based on the estimation of the influence of side-chain configurations on protease affinity, the RI-type inhibitors containing a D-allo-Ile residue in the corresponding substrate sequence, instead of a D-Ile residue, were synthesized via 9-fluorenylmethoxycarbonyl-based solid-phase peptide synthesis. Refolded recombinant HTLV-1 protease (1-116, L40I) was used for the simple and short evaluation of the inhibitory activities of the synthesized RI-type inhibitors. The results clearly indicated that mimicking the whole topology, comprising both the main- and side-chain structures of the parent inhibitor, is effective for the design of potent RI-modified protease inhibitors.

Microwave‐Assisted Synthesis of Hydroxyethylamine Dipeptide Isosteres.

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Microwave-assisted synthesis of hydroxyethylamine dipeptide isosteres

Microwave irradiation with calcium trifluoromethanesulfonate as a catalyst enabled epoxide opening with protected amino acids in high yields and with very short reaction times. Using this improved method, a series of hydroxyethyleneamine dipeptide isosteres was synthesized.

Evaluations of substrate specificity and inhibition at PR/p3 cleavage site of HTLV-1 protease

Core sequences necessary for substrate recognition and its inhibition at the PR/p3 site of HTLV-1 protease were clarified for the first time. From the cleavage rates of peptides containing a part of the PR/p3 site, a heptapeptide was found to be the minimal sequence required for substrate recognition. The use of synthetic inhibitors containing hydroxyethylamine dipeptide isostere indicated that a tetrapeptide sequence was necessary to achieve potent inhibition.

Epoxide opening with amino acids: improved synthesis of hydroxyethylamine dipeptide isosteres

The amino acid opening of epoxides, catalyzed by calcium trifluoromethanesulfonate with short reaction times is described. The method can be used in a straightforward route for the preparation of hydroxyethylamine dipeptide isosteres.

Indium-mediated atom-transfer and reductive radical cyclizations of iodoalkynes: synthesis and biological evaluation of HIV-protease inhibitors.

Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In (0.1 equiv) and I(2) (0.05 equiv) promotes atom-transfer 5-exo cyclization to give five-membered alkenyl iodides. In contrast, reaction with In (2 equiv) and I(2) (1 equiv) yields reductive 5-exo cyclization products via the same 5-exo cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity (IC(50) = 5-39 nM) against a wide spectrum of HIV strains, including multidrug-resistant variants.

Solid-phase synthesis of HTLV-1 protease inhibitors containing hydroxyethylamine dipeptide isostere.

An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure-activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the K(i) value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.

Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains.

Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K(i) = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC(50) = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P(1)-P(2) position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K(i) = 0.38 nM, IC(50) = 160 nM).

Synthesis of potent beta-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies.

Several beta-secretase inhibitors were designed based on hydroxyethylamine dipeptide isostere (HDI) structures and were synthesized by a methodology using the aza-Payne rearragement and O,N-acyl transfer reactions to study their structure-activity relationships. Among these pseudopeptides, effective compounds were developed as the first beta-secretase inhibitors containing the HDI transition state mimic with potent enzyme inhibitory activity (IC50 < 100 nM).

Efficient stereoselective synthesis of peptidomimetics containing hydroxyethylamine dipeptide isosteres utilizing the aza-Payne rearrangement and O, N-acyl transfer reactions

A novel methodology utilizing the aza-Payne rearrangement and O, N-intramolecular acyl transfer reactions for the synthesis of peptidomimetics containing hydroxyethylamine dipeptide isosteres (HDIs) is described. This methodology is useful for the stereoselective synthesis of HDI-containing pseudopeptides, and applicable to combinatorial chemistry using solid-phase techniques.

ChemInform Abstract: A Stereoselective Route to Hydroxyethylamine Dipeptide Isosteres.

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A stereoselective route to hydroxyethylamine dipeptide isosteres.

An efficient synthesis of stereodefined hydroxyethylamine dipeptide isosteres has been developed, utilizing a syn-selective Grignard addition and reductive amination as the key reactions.

Synthesis of enantiomerically pure cis and trans 2-aminocyclopentanecarboxylic acids. Use of proline replacements in potential HIV-protease inhibitors

The synthesis of the four diastereomeric 2-aminocyclopentanecarboxylic acids, their use as replacements for proline in potential HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere and the evaluation of the biological activity of these is described.

A convenient synthesis of 1-(S)-[1′-(S)-( t-butyloxycarbonylamino)-2′-phenylethyl]oxirane. A useful building block in the synthesis of HIV protease inhibitors

A new short route to epoxide 6b, a pivotal intermediate for the preparation of hydroxyethylamine dipeptide isosteres has been developed. Opening of the epoxide by anthranilic acid, followed by extensions in the P2 P3 -region gave the target compounds which were evaluated as HIV-1 protease inhibitors.

Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes

Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes