Abstract
In course of studies towards the discovery of selective inhibitors of MPtpA, a novel cyclic endiyne malonamic acid has been designed and synthesized. The synthesis involves a crucial intramolecular Knoevenagel reaction. The compound displayed a reversible non-competitive inhibition against MPtpA with inhibition constant K(i) of 22.5 μM. The enediyne acts as a recognition framework in inducing the inhibition and not as a reactive functional moiety. This was confirmed by comparing the inhibiting activity with that of the corresponding saturated cyclic non-enediyne analogue.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids, Cyclic / chemical synthesis
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Amino Acids, Cyclic / chemistry
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Amino Acids, Cyclic / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / metabolism
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Cyclization
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Drug Design
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Enediynes / chemical synthesis
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Enediynes / chemistry*
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Enediynes / pharmacology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Malonates / chemical synthesis
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Malonates / chemistry
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Malonates / pharmacology
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Models, Molecular
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Mycobacterium tuberculosis / enzymology*
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Protein Binding
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / metabolism
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Tuberculosis / drug therapy
Substances
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Amino Acids, Cyclic
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Bacterial Proteins
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Enediynes
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Enzyme Inhibitors
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Malonates
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MptpA protein, Mycobacterium tuberculosis
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malonamic acid
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Protein Tyrosine Phosphatases