Abstract
Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.
Keywords:
Hsp90; fluorinated compounds; geldanamycin; inhibitors; mutasynthesis; single molecule force spectroscopy.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Benzoquinones / chemistry*
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Calorimetry / methods
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Cell Line, Tumor / drug effects
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Cell Proliferation / drug effects
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Fluorobenzenes / metabolism
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Fluorobenzenes / pharmacology
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Lactams, Macrocyclic / chemistry*
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Magnetic Resonance Spectroscopy
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Microscopy, Atomic Force
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Models, Molecular
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Quinones / chemistry
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Streptomyces / genetics
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Streptomyces / metabolism*
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meta-Aminobenzoates / metabolism
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meta-Aminobenzoates / pharmacology
Substances
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Antineoplastic Agents
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Benzoquinones
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Fluorobenzenes
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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Quinones
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meta-Aminobenzoates
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geldanamycin