Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition-Elimination–Oxa-Michael Reactions

10.26434/chemrxiv.14679702.v2 ◽

2021 ◽

Author(s):

Tomislav Krolo ◽

Aditya Bhattacharyya ◽

Oliver Reiser

Keyword(s):

Visible Light ◽

Protease Inhibitors ◽

Carboxylic Acids ◽

Michael Reaction ◽

Conjugate Addition ◽

Cyclic Ether ◽

Synthetic Route ◽

Michael Reactions ◽

Synthetic Strategy ◽

Hiv 1

A novel photocatalytic decarboxylative radical conjugate addition-elimination-oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones has been developed to construct diverse cyclopentanonyl-fused functionalized cyclic ether derivatives in the presence of an inexpensive organic photocatalyst. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-Amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC 50 values.

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Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition-Elimination–Oxa-Michael Reactions

10.26434/chemrxiv.14679702 ◽

2021 ◽

Author(s):

Tomislav Krolo ◽

Aditya Bhattacharyya ◽

Oliver Reiser

Keyword(s):

Visible Light ◽

Protease Inhibitors ◽

Carboxylic Acids ◽

Michael Reaction ◽

Conjugate Addition ◽

Cyclic Ether ◽

Synthetic Route ◽

Michael Reactions ◽

Synthetic Strategy ◽

Hiv 1

A novel photocatalytic decarboxylative radical conjugate addition-elimination-oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones has been developed to construct diverse cyclopentanonyl-fused functionalized cyclic ether derivatives in the presence of an inexpensive organic photocatalyst. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-Amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC 50 values.

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Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition–Elimination–Oxa-Michael Reactions

Organic Letters ◽

10.1021/acs.orglett.1c01964 ◽

2021 ◽

Author(s):

Tomislav Krolo ◽

Aditya Bhattacharyya ◽

Oliver Reiser

Keyword(s):

Visible Light ◽

Protease Inhibitors ◽

Conjugate Addition ◽

Michael Reactions ◽

Hiv 1

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GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1In Vitroand Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01420-13 ◽

2013 ◽

Vol 57 (12) ◽

pp. 6110-6121 ◽

Cited By ~ 16

Author(s):

Pedro Miguel Salcedo Gómez ◽

Masayuki Amano ◽

Sofiya Yashchuk ◽

Akira Mizuno ◽

Debananda Das ◽

...

Keyword(s):

Protease Inhibitors ◽

Blood Brain Barrier ◽

Wide Spectrum ◽

Laboratory Strain ◽

Cyclic Ether ◽

Brain Barrier ◽

Blood Brain ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACTWe designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand,bis-tetrahydrofuranylurethane (bis-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1LAI(50% effective concentrations [EC50s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC50s], 17.5 and 37.0 μM, respectively, in CD4+MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1NL4-3variants selected by up to 5 μM lopinavir (EC50s, 0.03 and 0.03 μM, respectively) and atazanavir (EC50s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC50in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC50s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (logP) and distribution (logD) coefficients of −0.14 and −0.29, respectively. Thein vitroblood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10−6and 61.8 × 10−6cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variantsin vitroand suggest that two fluorine atoms added to theirbis-THF moieties may well enhance their penetration across the BBB.

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Catalytic Asymmetric Conjugate Addition of Carboxylic Acids via Oxa-Michael Reaction of Peroxy Hemiacetals followed by Kornblum DeLaMare Fragmentation

Organic Letters ◽

10.1021/acs.orglett.6b02463 ◽

2016 ◽

Vol 18 (20) ◽

pp. 5220-5223 ◽

Cited By ~ 16

Author(s):

Biswajit Parhi ◽

Sanjay Maity ◽

Prasanta Ghorai

Keyword(s):

Carboxylic Acids ◽

Michael Reaction ◽

Conjugate Addition ◽

Catalytic Asymmetric

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An oral high dose of cholecalciferol restores vitamin D status in deficient postmenopausal HIV-1 infected women independently of protease inhibitors therapy

Endocrine Abstracts ◽

10.1530/endoabs.37.ep293 ◽

2015 ◽

Author(s):

Jessica Pepe ◽

Ivano Mezzaroma ◽

Alessandra Fantauzzi ◽

Mario Falciano ◽

Alessandra Salotti ◽

...

Keyword(s):

Vitamin D ◽

Protease Inhibitors ◽

High Dose ◽

Vitamin D Status ◽

Hiv 1

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Generation of Phosphoranyl Radicals via Photoredox Catalysis Enables Voltage–Independent Activation of Strong C–O Bonds

10.26434/chemrxiv.6349253 ◽

2018 ◽

Author(s):

Erin Stache ◽

Alyssa B. Ertel ◽

Tomislav Rovis ◽

Abigail G. Doyle

Keyword(s):

Carboxylic Acids ◽

Functional Groups ◽

Single Step ◽

Direct Access ◽

Photoredox Catalysis ◽

Acyl Radical ◽

Synthetic Strategy ◽

Acyl Radicals ◽

Benzyl Radicals ◽

Aliphatic Carboxylic Acids

Alcohols and carboxylic acids are ubiquitous functional groups found in organic molecules that could serve as radical precursors, but C–O bonds remain difficult to activate. We report a synthetic strategy for direct access to both alkyl and acyl radicals from these ubiquitous functional groups via photoredox catalysis. This method exploits the unique reactivity of phosphoranyl radicals, generated from a polar/SET crossover between a phosphine radical cation and an oxygen centered nucleophile. We first show the desired reactivity in the reduction of benzylic alcohols to the corresponding benzyl radicals with terminal H-atom trapping to afford the deoxygenated product. Using the same method, we demonstrate access to synthetically versatile acyl radicals which enables the reduction of aromatic and aliphatic carboxylic acids to the corresponding aldehydes with exceptional chemoselectivity. This protocol also transforms carboxylic acids to heterocycles and cyclic ketones via intramolecular acyl radical cyclizations to forge new C–O, C–N and C–C bonds in a single step.

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