Merck Frosst Center for Therapeutic Research

Kirkland, Canada

Merck Frosst Center for Therapeutic Research

Kirkland, Canada

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Wang H.,Merck Frosst Center for Therapeutic Research | Claveau D.,Merck Frosst Center for Therapeutic Research | Vaillancourt J.P.,Merck Frosst Center for Therapeutic Research | Roemer T.,Merck Frosst Center for Therapeutic Research | And 2 more authors.
Nature Chemical Biology | Year: 2011

Connecting bacterial growth inhibitors to molecular targets at the whole-cell level is a major impediment to antibacterial development. Herein we report the design of a highly efficient and versatile bacteriophage-based mariner transposon delivery system in Staphylococcus aureus for determining inhibitor mode of action. Using bacteriophage-mediated delivery of concatameric minitransposon cassettes, we generated nonclonal transposant libraries with genome-wide insertion-site coverage in either laboratory or methicillin- resistant strain backgrounds and screened for drug resistance in situ on a single agar plate in one step. A gradient of gene-target expression levels, along with a correspondingly diverse assortment of drug-resistant phenotypes, was achieved by fitting the transposon cassette with a suite of outward-facing promoters. Using a panel of antibiotics, we demonstrate the ability to unveil not only an inhibitor's molecular target but also its route of cellular entry, efflux susceptibility and other off-target resistance mechanisms. © 2011 Nature America, Inc. All rights reserved.


Levesque P.,Merck Frosst Center for Therapeutic Research | Fournier P.-A.,Merck Frosst Center for Therapeutic Research
Journal of Organic Chemistry | Year: 2010

A mild, efficient, and simple method for the synthesis of 3-ethoxycarbonylindoles has been developed. Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords the indole core. As opposed to other common approaches for the synthesis of indole, this method displays both excellent functional group tolerance and perfect regiochemical control. This allowed the synthesis of a variety of useful indole building blocks from 2-aminobenzaldehydes derived from readily available anthranilic acids. © 2010 American Chemical Society.


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as -OH, -SH, or -NHR (R = alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner. © 2011 Elsevier Ltd. All rights reserved.


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed an efficient one-pot multistep sequence to the synthesis of 3-aminoindolizine derivatives by using Hantzsch ester (9) as a mild hydride transfer agent. The reaction scope was investigated and the effect of substrates on reaction outcomes was discussed.


Truong V.L.,Merck Frosst Center for Therapeutic Research | Morrow M.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2010

Condensation of o-iodobenzaldehydes 1a_c with amidine hydrochlorides 2a_p under ligand-free copper-catalyzed Ullmann N-arylation conditions afforded the corresponding quinazolines 3a-r in good to excellent yields. © 2009 Elsevier Ltd. All rights reserved.


Molinaro C.,Merck Frosst Center for Therapeutic Research | Guilbault A.-A.,Merck Frosst Center for Therapeutic Research | Kosjek B.,Merck And Co.
Organic Letters | Year: 2010

A practical procedure for the enzymatic resolution of 2-alkyl-2-aryl- disubstituted epoxides using the Codex HHDH P2E2 enzyme and sodium azide is reported. This method allowed the synthesis of novel regio-and enantioselective 1-azido-2-arylpropan-2-ols in excellent yields. Furthermore, these intermediates were used for the preparation of enantiomerically enriched amino alcohols and aziridines containing a tertiary center. © 2010 American Chemical Society.


Christian N.,Merck Frosst Center for Therapeutic Research | Aly S.,Merck Frosst Center for Therapeutic Research | Belyk K.,Merck And Co.
Journal of the American Chemical Society | Year: 2011

The highly enantioselective catalytic asymmetric addition of aryl and alkenylboronic acids to N-benzylnicotinate salt 1 is described. The dihydropyridine 2 reaction products can be converted to synthetically useful piperidines. Application of the methodology to the preparation of enantioenriched quaternary chiral centers is also discussed. © 2011 American Chemical Society.


Levesque J.F.,Merck Frosst Center for Therapeutic Research
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Xenobiotics, including therapeutic agents, can produce a variety of beneficial, as well as adverse, effects in mammals. One potential source of drug-mediated toxicity stems from metabolic activation of the parent compound, typically catalyzed by one or more members of the cytochrome P450 family of enzymes. The resulting electrophile, if not quenched by low molecular weight endogenous nucleophiles, can form covalent adducts to cellular proteins, potentially resulting in enzyme inactivation, cell death, or formation of an immunogenic species. The toxicological consequences of exposure to such reactive intermediates range from mild inflammation to organ failure, anaphylaxis, and death. At Merck Research Laboratories, the potential of drug candidates to bind covalently to proteins is evaluated at the lead optimization stage of drug discovery by incubating a radiolabeled analog of the compound in question with liver microsomal preparations (under oxidative conditions) or whole cells (full cellular metabolic capability), typically derived from rat and human liver. A semi-automated method based on the Brandel Harvester technique then is used to measure the formation of covalent adducts of the test compound to liver proteins. This assay is viewed as an important component of drug discovery programs, since the findings are employed to guide specific efforts to abrogate bioactivation issues through informed structural modification of lead compounds.


Powell D.A.,Merck Frosst Center for Therapeutic Research | Fan H.,Merck Frosst Center for Therapeutic Research
Journal of Organic Chemistry | Year: 2010

A room-temperature, copper-catalyzed amination of primary benzylic C?H bonds with primary and secondary sulfonamides is described. The reaction is applicable to the coupling of a range of primary and secondary benzylic hydrocarbons with a diverse set of sulfonamides and is tolerant of substitution on both coupling partners. Factors which influence the selectivity of C?H functionalization between primary and secondary sites are examined. © 2010 American Chemical Society.


Chang S.,Merck Frosst Center for Therapeutic Research | Lee E.E.,Merck Frosst Center for Therapeutic Research
Synthesis | Year: 2010

The addition of Grignard reagents to cyclic sulfamidate imines has been developed as a facile method for the synthesis of N-substituted quaternary sulfamidates. By way of ring opening with an appropriate nucleophile, versatile synthons for 1,2-amino alcohols, 1,2-diamines, and β-amino acids are produced. © Georg Thieme Verlag Stuttgart · New York.

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