A5060980612- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Click Chemistry and Applications
- Chemical synthesis and alkaloids
- Viral gastroenteritis research and epidemiology
- Fluorine in Organic Chemistry
- Synthetic Organic Chemistry Methods
- HIV-related health complications and treatments
- Telomeres, Telomerase, and Senescence
- HIV/AIDS Research and Interventions
- Quinazolinone synthesis and applications
- DNA Repair Mechanisms
- Crystallography and molecular interactions
- Biochemical and Molecular Research
- Cyclopropane Reaction Mechanisms
- PARP inhibition in cancer therapy
- Traditional and Medicinal Uses of Annonaceae
- RNA and protein synthesis mechanisms
- Animal Virus Infections Studies
- Medicinal Plants and Neuroprotection
- Autophagy in Disease and Therapy
- Carbohydrate Chemistry and Synthesis
University of Pittsburgh
2018-2025
Purdue University West Lafayette
2013-2020
Boehringer Ingelheim (Germany)
2013
Abstract HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes an exchange a sulfur oxygen, scission bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan mono- or bis-fluorine atoms around DRV’s scaffold. X-ray structural analyses complexed wild-type Protease (PR WT ) and...
Design, synthesis, and evaluation of a new class exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity drug-resistance profiles. In fact, this inhibitor showed several orders magnitude improved over the FDA approved drug darunavir. This incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as P2 ligand aminobenzothiazole P2' with (R)-hydroxyethylsulfonamide isostere. The for has been synthesized efficiently in...
Abstract Telomeres are hypersensitive to the formation of common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 MUTYH glycosylases initiate base excision repair (BER) remove 8oxoG or prevent mutation. Here, we show loss inhibition, loss, partially rescues telomeric 8oxoG-induced premature senescence associated proinflammatory responses, while both causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses fragility...
The development of zinc-mediated and -catalyzed asymmetric propargylations trifluoromethyl ketones with a propargyl borolane the N-isopropyl-l-proline ligand is presented. methodology provided moderate to high stereoselectivity was successfully applied on multikilogram scale for synthesis Glucocorticoid agonist BI 653048. A mechanism boron–zinc exchange proposed supported by modeling at density functional level theory. water acceleration effect zinc-catalyzed propargylation discovered, which...
Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced transmission at very high rates. However, certain who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due adverse effects emergence drug-resistant variants. Here, we report GRL-142, a novel protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which...
Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based incorporated unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as P2-ligand, a cyclopropylaminobenzothiazole P2'-ligand,...
The design, synthesis, and biological evaluation of a series HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in active site. Inhibitors 16a 16f showed excellent enzyme inhibitory antiviral activity, although incorporation sulfone functionality resulted decrease potency. Both maintained activity against panel multidrug resistant variants. A...
The design, synthesis, and biological evaluation of a new class HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands variety sulfonamide derivatives P2′ are described. A number ring sizes various substituent effects were investigated to enhance ligand–backbone interactions in active site. Inhibitors 5c 5d this unprecedented 6–5–5 system ligand, an aminobenzothiazole difluorophenylmethyl P1 ligand exhibited exceptional enzyme inhibitory...
An enantioselective total synthesis of (+)-amphirionin-4 has been accomplished in a convergent manner. The features an efficient enzymatic lipase resolution to access the tetrahydrofuranol core optically active form. functionalized tetrahydrofuran derivative was synthesized via oxocarbenium ion-mediated highly diastereoselective syn-allylation reaction. polyene side chain using Stille coupling reactions. Nozaki–Hiyama–Kishi utilized construct C-8 stereocenter and complete (+)-amphirionin-4.
We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) P2'-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 P2' ligands, respectively. GRL-003-15 have
Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and acute production 8oxoG damage at telomeres is sufficient drive rapid cellular senescence. OGG1 MUTYH glycosylases initiate base excision repair (BER) sites remove or prevent mutation. Here, we show loss inhibition, loss, partially rescues telomeric 8oxoG-induced senescence, both results in a near complete rescue. Loss these also suppresses telomere fragility dysfunction, indicating that single-stranded...
ABSTRACT We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing tricycle (cyclohexyl- bis -tetrahydrofuranylurethane [THF]) and sulfonamide isostere, is highly active against laboratory strains primary clinical isolates (50% effective concentration [EC 50 ], 0.0019 to 0.0036 μM), with minimal cytotoxicity cytotoxic [CC 21.0 μM). GRL-0739 blocked the infectivity replication of NL4-3 variants selected by concentrations up 5 μM ritonavir or atazanavir (EC , 0.035...
A series of potent HIV-1 protease inhibitors with novel P2-ligands have been designed and synthesized.
In a radical departure from the classical E1–E2–E3 three-enzyme mediated ubiquitination of eukaryotes, recently described bacterial enzymes SidE family Legionella pneumophila effectors utilize NAD+ to ligate ubiquitin onto target substrate proteins. This outcome is achieved via two-step mechanism involving (1) ADP ribosylation followed by (2) phosphotransfer serine residue. Here, using fluorescent analogues as well synthetic mimics, we have developed continuous assays enabling real-time...
A four-step synthesis of the FDA-approved anticancer agent gefitinib was developed starting from 2,4-dichloro-6,7-dimethoxyquinazoline. Reaction temperatures were highly practical (0–55 °C), and chromatographic purifications avoided. The ionic liquid trimethylammonium heptachlorodialuminate used to monodemethylate dimethoxyquinazoline core. In final step, a selective dehalogenation employed provide in 14% overall yield on gram scale.
Abstract Three cis ‐selective Co(II)‐salen complexes have been developed for the asymmetric cyclopropanation of para ‐fluorinated styrenes with ethyl diazoacetate. Increasing steric reach C 2 ‐symmetric ligand side chains improved enantiomeric ratio reaction from 28:1 to 66:1. The methodology was exemplified by gram‐scale synthesis a lead compound treatment castration‐resistant prostate cancer (CRPC), as well structurally related analog.