Solid phase synthesis of hydroxyethylamine peptide bond isosteres: Synthesis of the potent HIV-1 protease inhibitor JG365

doi:10.1016/S0040-4039(00)91592-2

Tetrahedron Letters

Volume 33, Issue 7, 11 February 1992, Pages 977-980

https://doi.org/10.1016/S0040-4039(00)91592-2 Get rights and content

Abstract

A protocl has been developed for the generation of hydroxyethylamine peptide bond isosteres in a polymer-supported synthesis. This has been used to produce the potent HIV-1 Protease inhibitor JG365 rapidly and in good yield.

A protocol has been developed for the rapid generation of hydroxyethylamine peptide bond isosteres in a polymer-supported synthesis in good yield.

References (21)

A.M. Skalka
Cell
(1989)
P.L. Darke
J. Biol. Chem.
(1989)
J. Kay et al.
Biochim. Biophys. Acta
(1990)
T.J. McQuade
Science
(1989)
T.D. Meek
Nature
(1990)
N.A. Roberts
Science
(1990)
M.V. Toth et al.
J.D. Godfrey et al.
J. Org. Chem.
(1986)
A.J. Barrett et al.
Y. Sasaki et al.
Peptides
(1987)
Y. Sasaki et al.
J. Med. Chem.
(1987)
N.A. Roberts
Science
(1990)
D.H. Rich et al.
J. Med. Chem.
(1990)

There are more references available in the full text version of this article.

Cited by (26)

Protein backbone engineering through total chemical synthesis: New insight into the mechanism of HIV-1 protease catalysis
2000, Tetrahedron
Total chemical synthesis by convergent chemical ligation was used to prepare a ‘backbone engineered’ 202-residue covalent dimer asymmetric form of the HIV-1 protease molecule. The Gly49-Ile50 peptide bond backbone –N(H)– atom, critically involved in H-bonding to substrates, was specifically replaced by an –O– atom in one flap only. The resulting enzyme analogue retained full intrinsic activity, demonstrating that enzyme–substrate hydrogen bonding at the Gly49-Ile50 peptide bond in only a single flap is sufficient for normal catalytic function.
Solid-phase synthesis of hydroxyethylamine angiotensin analogues
1997, Peptides
Chambers, S. L., R. Ronald, J. M. Hanesworth, D. H. Kinder and J. W. Harding. Solid-phase synthesis of hydroxyethylamine angiotensin analogues. Peptides 18(4) 505–512, 1997.—Three hydroxylethylamine analogues of angiotensins II, III, and IV were prepared by solid-phase methods. The resin-bound peptide was alkylated with the iodomethylketone derivative of the N-terminal amino acid, followed by reduction to the alcohol using sodium borohydride. The iodomethylketones can be made in good yields from commerically available N-protected amino acids. The compounds were evaluated for their ability to displace labeled angiotensins from bovine adrenal membranes, and their metabolic stability tested in kidney homogenates and aminopeptidase M preparations. The hydroxyethylamine amide bond replacement reduced the affinity of the analogues; however, they were substantially more stable to enzymatic degradation.
Chapter 31. Solid-Phase Synthesis: Applications to Combinatorial Libraries
1996, Annual Reports in Medicinal Chemistry
This chapter discusses a comprehensive survey of templates and skeletons for which a solid-phase synthesis has been reported for library synthesis. The chapter also discusses a survey of the reactions that have been performed on solid support along with a discussion on some issues specific to solid-phase synthesis. Libraries of discrete compounds have been prepared by parallel synthesis in a spatially addressable fashion, where compound location indicates the compound structure. For peptides and oligonucleotides, rapid and sensitive sequencing strategies are available for determining the compound structure. The backbones or templates, for which solid-phase synthesis has been reported, are categorized as: nonpeptide oligomers, privileged structures, novel templates, designed templates targeted toward a particular receptor or enzyme class, and structures for lead optimization. Many reactions have been demonstrated on the solid-support. These reactions are categorized into carbon-heteroatom bond forming reactions, carbon-carbon bond forming reactions, cycloadditions, and multicomponent reactions. The linkage element for covalently attaching a compound to the solid support deserves special consideration. The linker should be stable to the reaction conditions employed in the synthesis sequence, but should be cleavable under conditions that do not degrade the product. Linkage to the solid support is generally accomplished, using a functional group that is a part of the targeted molecule or that is appended onto the structure. Many different analytical techniques are currently being used to evaluate the solid-phase reactions or compounds bound to the solid support. Functional group titration is often used to monitor the reactions. Many advances continue to be made in the synthesis of small-molecule libraries on solid supports, including the development of new support materials. Equally important efforts are being made in the computational methods for library design and database management, analytical evaluation, automation and instrumentation for synthesis and purification, and methods for high-throughput biological evaluation.
The solid phase synthesis of dihydro- and tetrahydroisoquinolines
1995, Tetrahedron Letters
Novel angiotensin converting enzyme inhibitors containing α-hydroxy ketomethylene dipeptide isosteres
1994, Bioorganic and Medicinal Chemistry Letters
CrCl<inf>2</inf> mediated allylation of N-protected α-amino aldehydes. A versatile synthesis of polypeptides containing an hydroxyethylene isostere
1994, Tetrahedron Letters
Differently substituted allylic bromides react with N-protected amino aldehydes to give intermediate products for the synthesis of hydroxyethylene dipeptide isosteres. The low stereoselectivity of this reaction can be improved using aldehydes protected with hindered groups. This reaction can be efficiently applied to oligopetide aldehydes. We describe a protocol, for the preparation of peptides containing an hydroxyethylene isostere, which allows a rapid variations of the aminoacid sequence

View all citing articles on Scopus

View full text

Solid phase synthesis of hydroxyethylamine peptide bond isosteres: Synthesis of the potent HIV-1 protease inhibitor JG365

Abstract

Cell

J. Biol. Chem.

Biochim. Biophys. Acta

Science

Nature

Science

J. Org. Chem.

Peptides

J. Med. Chem.

Science

J. Med. Chem.