Source:http://linkedlifedata.com/resource/pubmed/id/16506767
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
2006-3-1
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| pubmed:abstractText |
An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.
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| pubmed:grant | |
| pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-10801476,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-10822541,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11456806,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11562292,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11579438,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11807177,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11933229,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-11965380,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-12889959,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-15053621,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-15101783,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-15700951,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-4331859,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-5124385,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-5124386,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-8979249,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16506767-9871529
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Dipeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Lactates,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Vancomycin,
http://linkedlifedata.com/resource/pubmed/chemical/alanylalanine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
0002-7863
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
8
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| pubmed:volume |
128
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
2885-92
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| pubmed:dateRevised |
2010-10-4
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| pubmed:meshHeading | |
| pubmed:year |
2006
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| pubmed:articleTitle |
Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding.
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| pubmed:affiliation |
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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