Abstract
A four-enzyme catalyzed hydroxy regioisomerization of anthracycline was integrated into the biosynthetic pathway of aclacinomycin A (ALM-A), to generate a series of iso-ALMs via directed combinatorial biosynthesis combined with precursor-directed mutasynthesis. Most of the newly acquired iso-ALMs exhibit obviously (1-5-fold) improved antitumor activity. Therefore, we not only developed iso-ALMs with potential as clinical drugs but also demonstrated the utility of this tailoring tool for modification of anthracycline antibiotics in drug discovery and development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aclarubicin / analogs & derivatives*
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Aclarubicin / biosynthesis
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Aclarubicin / chemistry
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Aclarubicin / pharmacology
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Antibiotics, Antineoplastic / biosynthesis
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Antibiotics, Antineoplastic / chemistry
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Antibiotics, Antineoplastic / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Molecular Conformation
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Polyketide Synthases / metabolism*
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Streptomyces / chemistry
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Streptomyces / metabolism
Substances
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Antibiotics, Antineoplastic
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aclacinomycins
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Aclarubicin
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Polyketide Synthases