Ir C–H Activation and Other Catalysis Applied to a Complex Drug Candidate

Bullock, Kenneth; Chong, P.; Davis, Roman; Elitzin, Vassil I.; Hatcher, Mark A.; Jackson, Mark; Liu, B.; Patterson, Daniel E.; Powers, Jackson; Salmons, Matthew; Tabet, Elie A.; Toczko, Matthew A.

doi:10.1007/s11244-012-9809-z

Cited by 6 publications

(3 citation statements)

References 8 publications

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“…We reasoned that placement of a fused cyclopropane ring such as that in a bicyclo[3.1.0]hexanone system might provide additional hydrophobic interactions necessary to maintain LasR potency while also providing robust chemical and metabolic stability. We synthesized the requisite (1 S ,3 S ,5 S )-3-aminobicyclo[3.1.0]hexan-2-one and corresponding 3-aminobicyclo[3.1.0]hexan-2-ols according to a published procedure and attached these new head groups to three different tail groups: the dodecanoyl side chain of 3OC 12 HSL (BB0231, BB0232, and BB0233), the 3-bromophenoxybutanoyl tail group found in mBTL (BB0020), and a novel 3-(methylsulfonyl)phenoxybutanoyl tail group in which the bromine of mBTL was replaced with a methylsulfone group (BB0126, BB0272, BB0273). We also prepared the analogue with the lactone head group found in 3OC 12 HSL and the 3-(methylsulfonyl)phenoxybutanoyl tail piece (BB0221).…”

Section: Resultsmentioning

confidence: 99%

An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor

et al. 2019

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Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein. Structural analyses of the LasR ligand binding domain complexed with representative synthetic agonists reveal two modes of ligand binding, one mimicking the canonical autoinducer binding arrangement and the other with the lactone head group rotated approximately 150°. Iterative mutagenesis combined with chemical synthesis reveals the amino acid residues and the chemical moieties, respectively, that are key to enabling each mode of binding. Simultaneous alteration of LasR residues Thr75, Tyr93, and Ala127 converts low-potency compounds into high-potency compounds and converts ligands that are nearly inactive into low-potency compounds. These results show that the LasR binding pocket displays significant flexibility in accommodating different ligands. The ability of LasR to bind ligands in different conformations, and in so doing, alter their potency as agonists, could explain the difficulties that have been encountered in the development of competitive LasR inhibitors.

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Section: Resultsmentioning

confidence: 99%

An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor

et al. 2019

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“…54,55 The zincation/iodination/ trifluoromethylation procedure has been carried out successfully on 300 g of starting material 18, which provided 17b in 86% isolated yield. 56,57 With the 7-CF 3 group installed on the pyrazolopyridine core (17a,b), the introduction of functionality at C(5) was now required. Iridium-catalyzed activation of aromatic C−H bonds has proven to be a useful method for the functionalization of related aromatic ring systems.…”

Section: ■ In Vivo Profiling Of the Lead 1amentioning

confidence: 99%

“…No 7-(trifluoromethyl)pyrazolopyridine analogues were available from commercial vendors; however, the des-CF 3 analogue 18 could be purchased and represented an attractive starting point. After some optimization, we found that 18 could be efficiently converted to 17b by a two-step procedure involving selective zincation/iodination at C(7) , followed by Cu-mediated trifluoromethylation of the iodo intermediate 19 (Scheme ). , The zincation/iodination/trifluoromethylation procedure has been carried out successfully on 300 g of starting material 18 , which provided 17b in 86% isolated yield. , …”

Section: Improving Potency Against Resistant Virusesmentioning

confidence: 99%

Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein

et al. 2013

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We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

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Methyl fluorosulfonyldifluoroacetate (MFSDA): An Underutilised Reagent for Trifluoromethylation

Clarke

McGlacken

2016

Chemistry A European J

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The introduction of fluorine groups to pharmaceutical compounds can have a dramatic effect on the lipophilicity and metabolic stability of the molecule in vivo. Around 20 % of drugs contain at least one fluorine atom. The trifluoromethyl group is known to have beneficial effects and can dramatically affect the biological activity when substituted for a methyl group, for example. In any case, the direct and late-stage introduction of a trifluoromethyl group is a powerful transformation in the tool box of the medicinal chemist. The use of methyl fluorosulfonyldifluoroacetate (MFSDA) as a relatively inexpensive reagent for trifluoromethylation was first reported in 1989; however, in our opinion it has been somewhat underutilised. Herein, a comprehensive review of trifluoromethylation using MFSDA is reported, which we hope will further expose readers to this useful reagent.

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Ir C–H Activation and Other Catalysis Applied to a Complex Drug Candidate

Cited by 6 publications

References 8 publications

An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor

An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor

Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein

Methyl fluorosulfonyldifluoroacetate (MFSDA): An Underutilised Reagent for Trifluoromethylation

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