Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation
Abstract
The structure–based design, synthesis, biological evaluation, and X–ray structural studies of fluorine–containing HIV–1 protease inhibitors are described. The synthesis of both enantiomers of the gem–difluoro–bis–THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)–4,4–difluorohexahydrofuro[2,3–b]furan–3–yl(2S,3R)–3–hydroxy–4–((N–isobutyl–4–methoxyphenyl)sulfonamido)–1–phenylbutan–2–yl) carbamate (3) and (3R,3aS,6aS)–4,4–difluorohexahydrofuro[2,3–b]furan–3–yl(2S,3R)–3–hydroxy–4–((N–isobutyl–4–aminophenyl)sulfonamido)phenylbutan–2–yl) carbamate (4), exhibited HIV–1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV–1LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high–resolution X–ray structure of inhibitor 4 in complex with HIV–1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV–1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis–THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.
- Authors:
-
- Purdue Univ., West Lafayette, IN (United States)
- Georgia State Univ., Atlanta, GA (United States)
- Kumamoto Univ. School of Medicine (Japan)
- Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); US National Inst. of Health; US National Cancer Inst.; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Welfare, and Labor of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Kumamoto Univ.) of Monbu‐Kagakusho
- OSTI Identifier:
- 1245842
- Grant/Contract Number:
- GM53386; GM62920; H15‐AIDS‐001
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ChemMedChem
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 1860-7179
- Publisher:
- ChemPubSoc Europe
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; antiviral agents; blood–brain barrier; HIV‐1 protease; inhibitors; ligands; multidrug resistance
Citation Formats
Ghosh, Arun K., Yashchuk, Sofiya, Mizuno, Akira, Chakraborty, Nilanjana, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Gomez, Pedro Miguel Salcedo, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation. United States: N. p., 2014.
Web. doi:10.1002/cmdc.201402358.
Ghosh, Arun K., Yashchuk, Sofiya, Mizuno, Akira, Chakraborty, Nilanjana, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Gomez, Pedro Miguel Salcedo, Amano, Masayuki, Weber, Irene T., & Mitsuya, Hiroaki. Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation. United States. https://doi.org/10.1002/cmdc.201402358
Ghosh, Arun K., Yashchuk, Sofiya, Mizuno, Akira, Chakraborty, Nilanjana, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Gomez, Pedro Miguel Salcedo, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Tue .
"Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation". United States. https://doi.org/10.1002/cmdc.201402358. https://www.osti.gov/servlets/purl/1245842.
@article{osti_1245842,
title = {Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation},
author = {Ghosh, Arun K. and Yashchuk, Sofiya and Mizuno, Akira and Chakraborty, Nilanjana and Agniswamy, Johnson and Wang, Yuan-Fang and Aoki, Manabu and Gomez, Pedro Miguel Salcedo and Amano, Masayuki and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {The structure–based design, synthesis, biological evaluation, and X–ray structural studies of fluorine–containing HIV–1 protease inhibitors are described. The synthesis of both enantiomers of the gem–difluoro–bis–THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)–4,4–difluorohexahydrofuro[2,3–b]furan–3–yl(2S,3R)–3–hydroxy–4–((N–isobutyl–4–methoxyphenyl)sulfonamido)–1–phenylbutan–2–yl) carbamate (3) and (3R,3aS,6aS)–4,4–difluorohexahydrofuro[2,3–b]furan–3–yl(2S,3R)–3–hydroxy–4–((N–isobutyl–4–aminophenyl)sulfonamido)phenylbutan–2–yl) carbamate (4), exhibited HIV–1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV–1LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high–resolution X–ray structure of inhibitor 4 in complex with HIV–1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV–1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis–THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.},
doi = {10.1002/cmdc.201402358},
journal = {ChemMedChem},
number = 1,
volume = 10,
place = {United States},
year = {Tue Oct 21 00:00:00 EDT 2014},
month = {Tue Oct 21 00:00:00 EDT 2014}
}
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Works referencing / citing this record:
Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors
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