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}
}
Web of Science
Works referenced in this record:
Fluorine-containing organozinc reagents. V.
journal, January 1988
- Greuter, Hans; Lang, Robert W.; Romann, Andres J.
- Tetrahedron Letters, Vol. 29, Issue 27
Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure
journal, August 2011
- Ghosh, Arun K.; Chapsal, Bruno D.; Parham, Garth L.
- Journal of Medicinal Chemistry, Vol. 54, Issue 16
PRODRG : a tool for high-throughput crystallography of protein–ligand complexes
journal, July 2004
- Schüttelkopf, Alexander W.; van Aalten, Daan M. F.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 8
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains
journal, April 2004
- Tie, Yunfeng; Boross, Peter I.; Wang, Yuan-Fang
- Journal of Molecular Biology, Vol. 338, Issue 2
Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes
journal, January 2001
- Mahalingam, Bhuvaneshwari; Louis, John M.; Hung, Jason
- Proteins: Structure, Function, and Genetics, Vol. 43, Issue 4
Darunavir (Prezista): A HIV-1 Protease Inhibitor for Treatment of Multidrug-Resistant HIV
book, January 2010
- Ghosh, Arun K.; Martyr, Cuthbert D.
- Modern Drug Synthesis
Modelling of the blood–brain barrier in drug discovery and development
journal, August 2007
- Cecchelli, Romeo; Berezowski, Vincent; Lundquist, Stefan
- Nature Reviews Drug Discovery, Vol. 6, Issue 8
Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus–infected patients
journal, January 2006
- Langford, Dianne; Marquie-Beck, Jennifer; de Almeida, Sergio
- Journal of Neurovirology, Vol. 12, Issue 2
A short history of SHELX
journal, December 2007
- Sheldrick, George M.
- Acta Crystallographica Section A Foundations of Crystallography, Vol. 64, Issue 1, p. 112-122
Fluorine in medicinal chemistry
journal, January 2008
- Purser, Sophie; Moore, Peter R.; Swallow, Steve
- Chem. Soc. Rev., Vol. 37, Issue 2
A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site
journal, February 2002
- Yoshimura, K.; Kato, R.; Kavlick, M. F.
- Journal of Virology, Vol. 76, Issue 3
Synthesis of 2‘,3‘-Dideoxy-6‘,6‘-difluorocarbocyclic Nucleosides
journal, November 2004
- Yang, Yan-Yan; Meng, Wei-Dong; Qing, Feng-Ling
- Organic Letters, Vol. 6, Issue 23
Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV
journal, January 2012
- Ghosh, Arun K.; Anderson, David D.; Weber, Irene T.
- Angewandte Chemie International Edition, Vol. 51, Issue 8
Combined use of computational chemistry, NMR screening, and X-ray crystallography for identification and characterization of fluorophilic protein environments
journal, November 2010
- Vulpetti, Anna; Schiering, Nikolaus; Dalvit, Claudio
- Proteins: Structure, Function, and Bioinformatics, Vol. 78, Issue 16
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
A simple, continuous fluorometric assay for HIV protease
journal, December 1990
- Toth, Mihaly V.; Marshall, Garland R.
- International Journal of Peptide and Protein Research, Vol. 36, Issue 6
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance
journal, September 2006
- Ghosh, Arun K.; Ramu Sridhar, Perali; Kumaragurubaran, Nagaswamy
- ChemMedChem, Vol. 1, Issue 9
Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus
journal, August 2005
- Kramer-Hämmerle, Susanne; Rothenaigner, Ina; Wolff, Horst
- Virus Research, Vol. 111, Issue 2
Synthesis of 3‘,3‘-Difluoro-2‘- hydroxymethyl-4‘,5‘-Unsaturated Carbocyclic Nucleosides
journal, December 2007
- Yang, Yan-Yan; Xu, Jun; You, Zheng-Wei
- Organic Letters, Vol. 9, Issue 26
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance
journal, January 2008
- Ghosh, Arun K.; Chapsal, Bruno D.; Weber, Irene T.
- Accounts of Chemical Research, Vol. 41, Issue 1
A graphical user interface to the CCP 4 program suite
journal, June 2003
- Potterton, Elizabeth; Briggs, Peter; Turkenburg, Maria
- Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 7
M ETABOLISM OF F LUORINE -C ONTAINING D RUGS
journal, April 2001
- Park, B. Kevin; Kitteringham, Neil R.; O'Neill, Paul M.
- Annual Review of Pharmacology and Toxicology, Vol. 41, Issue 1
Pericytes from Brain Microvessels Strengthen the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells
journal, September 2007
- Nakagawa, Shinsuke; Deli, Mária A.; Nakao, Shinobu
- Cellular and Molecular Neurobiology, Vol. 27, Issue 6
Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease †
journal, September 2007
- Wang, Yuan-Fang; Tie, Yunfeng; Boross, Peter I.
- Journal of Medicinal Chemistry, Vol. 50, Issue 18
Neurological complications of HIV infection
journal, September 2005
- McArthur, Justin C.; Brew, Bruce J.; Nath, Avi
- The Lancet Neurology, Vol. 4, Issue 9
Fluorine Bonding — How Does It Work In Protein−Ligand Interactions?
journal, September 2009
- Zhou, Peng; Zou, Jianwei; Tian, Feifei
- Journal of Chemical Information and Modeling, Vol. 49, Issue 10
Fluorine substituent effects (on bioactivity)
journal, June 2001
- Smart, Bruce E.
- Journal of Fluorine Chemistry, Vol. 109, Issue 1
[16] SHELXL: High-resolution refinement
book, January 1997
- Sheldrick, George M.; Schneider, Thomas R.
- Methods in Enzymology
Fluorine in Medicinal Chemistry
journal, April 2004
- Böhm, Hans-Joachim; Banner, David; Bendels, Stefanie
- ChemBioChem, Vol. 5, Issue 5
HIV-Associated Neurological Disorders: A Guide to Pharmacotherapy
journal, January 2012
- Tan, Ik L.; McArthur, Justin C.
- CNS Drugs, Vol. 26, Issue 2
Verstärkung der Bindung an das Proteinrückgrat - ein fruchtbares Konzept gegen die Arzneimittelresistenz von HIV
journal, January 2012
- Ghosh, Arun K.; Anderson, David D.; Weber, Irene T.
- Angewandte Chemie, Vol. 124, Issue 8
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV
journal, December 2007
- Ghosh, Arun K.; Dawson, Zachary L.; Mitsuya, Hiroaki
- Bioorganic & Medicinal Chemistry, Vol. 15, Issue 24
Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro
journal, September 2003
- Koh, Y.; Nakata, H.; Maeda, K.
- Antimicrobial Agents and Chemotherapy, Vol. 47, Issue 10
Stereoselective Photochemical 1,3-Dioxolane Addition to 5- Alkoxymethyl-2(5 H )-furanone: Synthesis of Bis-tetrahydrofuranyl Ligand for HIV Protease Inhibitor UIC-94017 (TMC-114)
journal, November 2004
- Ghosh, Arun K.; Leshchenko, Sofiya; Noetzel, Marcus
- The Journal of Organic Chemistry, Vol. 69, Issue 23
Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere
journal, March 1998
- Ghosh, Arun K.; Kincaid, John F.; Cho, Wonhwa
- Bioorganic & Medicinal Chemistry Letters, Vol. 8, Issue 6
An efficient and stereoselective synthesis of platelet-activating factors and the enantiomers from D- and L- tartaric acids
journal, January 1982
- Fujita, Kagari; Nakai, Hisao; Kobayashi, Susumu
- Tetrahedron Letters, Vol. 23, Issue 34
GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration
journal, September 2013
- Salcedo Gómez, Pedro Miguel; Amano, Masayuki; Yashchuk, Sofiya
- Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 12
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Works referencing / citing this record:
Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors
journal, June 2018
- Ghosh, Arun K.; Brindisi, Margherita
- Asian Journal of Organic Chemistry, Vol. 7, Issue 8
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants
journal, March 2018
- Ghosh, Arun K.; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R.
- ChemMedChem, Vol. 13, Issue 8
Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications
journal, May 2019
- Amano, Masayuki; Salcedo-Gómez, Pedro Miguel; Yedidi, Ravikiran S.
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 7