Hydroxyethylene Dipeptide Isosteres Research Articles

ChemInform Abstract: A Convenient Approach to Hydroxyethylene Dipeptide Isosteres as Building Blocks for Enzyme Inhibitors.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Stereocontrolled Convergent Synthesis of Hydroxyethylene Dipeptide Isosteres by the Reaction of α-Amino Aldehyde with Alkoxytitanium Homoenolates.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis of Hydroxyethylene Dipeptide Isosteres That Mimic a Cyclic Amino Acid at the P1′ Subsite.

ChemInform Abstract: Synthesis of Hydroxyethylene Dipeptide Isosteres That Mimic a Cyclic Amino Acid at the P1′ Subsite.

ChemInform Abstract: Dipeptide Isosteres. Part 2. Synthesis of Hydroxyethylene Dipeptide Isostere Diastereomers from a Common γ-Lactone Intermediate. Preparation of Renin and HIV-1 Protease Inhibitor Transition State Mimics.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Diastereoselective Synthesis of the Key Lactone Intermediate (VI) for the Preparation of Hydroxyethylene Dipeptide Isosteres.

ChemInform Abstract: Diastereoselective Synthesis of the Key Lactone Intermediate (VI) for the Preparation of Hydroxyethylene Dipeptide Isosteres.

A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C 2 symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C 2-symmetric of the metathesis product 8 to obtain the required skeleton.

The P 1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin

Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P 1 motif were designed based on initial lead structures 1 and aliskiren ( 2). (P 3–P 1)-Benzamide derivatives such as 9a and 34, as well as the corresponding P 1 basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.

Synthesis of a Hydroxyethylene Dipeptide Isostere, a Core Unit of the HIV Protease Inhibitors Ritonavir and Lopinavir, and Its C-5 Epimer

A short synthesis of a hydroxyethylene dipeptide isostere, a core unit of the HIV protease inhibitors ritonavir and lopinavir, and its C-5 epimer is described.

Synthesis of β‐Secretase Inhibitors Containing a Hydroxyethylene Dipeptide Isostere.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of β‐Secretase Inhibitors Containing a Hydroxyethylene Dipeptide Isostere

β‐Secretase inhibitors with a Leu*Ala hydroxyethylene dipeptide (HED) isostere have been an especially interesting topic in recent years. In this study, a template compound 17 was synthesized, featuring truncation at the P2′ position and changes at P2 and P3, which differs from other reported potent inhibitors. The purpose was to explore optimal reaction conditions and construct an inhibitor library to investigate ideal protein–substrate interaction.

Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to ?-secretase

To develop probes for detecting the binding specificity between beta-secretase and substrate, and provide reliable biological activity data for further researching encircling substrate-based inhibitors. To prepare the inhibitors, the hydroxyethylene (HE) segment including P1 and P1'was synthesized after multi-step reactions; the combination of all segments was then completed through solid phase synthesis. Recombinant human beta-secretase ectodomain (amino acid residues 1-460) was expressed as a secreted protein with a C-terminal His tag in insect cells using baculovirus infection, and all compounds were evaluated in this beta-secretase enzyme assay. In order to understand the interaction in detail, the theoretical methods, namely molecular dynamics (MD) simulation and molecular mechanics-generalized-born surface area (MM-GBSA) analysis, were performed on the complex of beta-secretase and OM99-2 to obtain the geometrical and energetical information. We designed and constructed a positional scanning combinatorial library including 16 compounds; all members of the library were synthesized based on HE dipeptide isostere. Structure-activity relationship studies at the P4-P1 and P1' -P4'positions led to the discoveries of P and P'sides binding specificity and potent inhibitors 14, 18, and 22. The binding free energy on the whole system and every residue were compared to the biological assay result. The removal of P4' yielded inhibitor 22 (A3 *B2) with high potency; further truncation of P3'gave inhibitor 18 (A3 *B1) with equal activity, implying that the right side of the inhibitors play a less important role and could be easily simplified, while change on the P side may cause substantial results.

Intra- or Intercomplex Binding to the γ-Secretase Enzyme: A MODEL TO DIFFERENTIATE INHIBITOR CLASSES

Intra- or Intercomplex Binding to the γ-Secretase Enzyme: A MODEL TO DIFFERENTIATE INHIBITOR CLASSES

An Efficient, Stereoselective Synthesis of the Hydroxyethylene Dipeptide Isostere Core for the HIV Protease Inhibitor A-792611

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

Preorganization of the Hydroxyethylene Dipeptide Isostere: The Preferred Conformation in Solution Resembles the Conformation Bound to BACE

Conformational analysis in solution of beta-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with beta-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.

Synthesis of a Tripeptide Derivative Containing the Gln‐Arg Hydroxyethylene Dipeptide Isostere

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of a Gln‐Phe Hydroxyethylene Dipeptide Isostere.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Stereodivergent Synthesis of Hydroxyethylene Dipeptide Isostere via Highly Diastereoselective Epoxidation

Epoxidation of δ-amino-β,γ-unsaturated ester with tri­fluoroperacetic acid afforded its epoxide in a highly diastereo­selective manner. Subsequent stereodivergent epoxide opening reactions provided synthetic routes towards both the threo and erythro hydroxyethylene peptide isostere.

Novel Heterocyclic Analogues of the HIV‐1 Protease Inhibitor, Ritonavir.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of a Tripeptide Derivative Containing the Gln-Arg Hydroxyethylene Dipeptide Isostere

[structure: see text] The protected hydroxyethylene dipeptide isostere of Gln-Arg and the tripeptide derivative 1 were synthesized as components of potential peptidase inhibitors.

Synthesis of a Gln-Phe Hydroxy-ethylene Dipeptide Isostere

[structure: see text] The protected Gln-Phe hydroxyethylene dipeptide isostere 1 was synthesized as a precursor for preparation of potential inhibitors of Botulinum neurotoxin B metalloprotease. The method allows for the synthesis of additional hydroxyethylene dipeptide isosteres such as 2 with functionalized P1 side chains. The isosteres prepared were coupled with a dipeptide to produce protected pseudotetrapeptide derivatives.