Potent HIV-1 protease inhibitors: stereoselective synthesis of a dipeptide mimic
- 1 February 1993
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 58 (5) , 1025-1029
- https://doi.org/10.1021/jo00057a011
Abstract
The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.Keywords
This publication has 9 references indexed in Scilit:
- HIV protease: a novel chemotherapeutic target for AIDSJournal of Medicinal Chemistry, 1991
- Structure-based, C2 symmetric inhibitors of HIV proteaseJournal of Medicinal Chemistry, 1990
- Design, Activity, and 2.8 Å Crystal Structure of a C 2 Symmetric Inhibitor Complexed to HIV-1 ProteaseScience, 1990
- Affinity purification of the HIV-1 proteaseBiochemical and Biophysical Research Communications, 1989
- Conserved Folding in Retroviral Proteases: Crystal Structure of Synthetic HIV-1 ProteaseScience, 1989
- Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1Nature, 1989
- Active human immunodeficiency virus protease is required for viral infectivity.Proceedings of the National Academy of Sciences, 1988
- Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDSScience, 1984
- Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS)Science, 1983