New, Non‐quinone Fluorogeldanamycin Derivatives Strongly Inhibit Hsp90

Hermane, Jekaterina; Bułyszko, Ilona; Eichner, Simone; Sasse, Florenz; Collisi, Wera; Poso, Antti; Schax, Emilia; Walter, Johanna‐Gabriela; Scheper, Thomas; Kock, Klaus; Herrmann, Christian; Aliuos, Pooyan; Reuter, G.; Zeilinger, Carsten; Kirschning, Andreas

doi:10.1002/cbic.201402375

Cited by 19 publications

(27 citation statements)

References 62 publications

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“…Administration of structurally modified derivatives—so called mutasynthons—to these blocked mutants reconstitutes the substrate flow, which results in new metabolites. For the preparation of new reblastatin derivatives the use of a 3‐amino‐5‐hydroxybenzoic acid (−) mutant strain [AHBA(−)] of Streptomyces hygroscopicus was found to be ideally suited …”

Section: Resultsmentioning

confidence: 99%

“…Consequently, we assumed that LbHsp90 should also be a target for heat shock protein inhibitors related to geldanamycin and reblastatin. We used our ATP‐displacement assay as a screening tool and in selected cases complemented the assay data with isothermal titration calorimetry (ITC) measurements …”

Section: Resultsmentioning

confidence: 99%

“…This approach allowed us to determine the binding of fluorescence‐labelled ATP (Cy3‐ATP) as well as putative inhibitors that address the ATP binding site (Figure , bottom) and to carry out displacement measurements between ATP and the potential inhibitors . With this system to hand, we assayed the HsHsp90 and LbHsp90 inhibitory activities of new reblastatin derivatives and also of known reblastatin derivatives, as well as those of classical Hsp inhibitors such as radicicol, novobiocin and celastrol (Table ) . Concentrations were set at 500 n m against HsHsp90 and LbHsp90.…”

Section: Resultsmentioning

confidence: 99%

“…Dose–response curves for 1 c and reblastatin derivatives 15 and 16 that are representative examples for all compounds tested (Table ) are shown in Figure A (left) and B (array positions refer to compounds listed in Table ). Six compounds [radicicol ( 2 ), fluoro reblastatin derivatives 3 , 14 and 15 , the 18‐fluoro derivative (array position 16) and the 18‐bromo derivative (array position 8)] were identified as highly efficient binders for both heat shock proteins. Several points need to be stressed.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, 17‐aminoallylgeldanamycin ( 1 c , 17‐AAG), obtained by semisynthesis from 1 a , reached phase 2 clinical trials. Recently, we showed that the cytotoxic non‐quinone geldanamycin derivative 3 , obtained by a mutasynthetic approach, is able to bind to human Hsp90 with better affinity than 17‐AAG ( 1 c ); fluoro derivative 3 showed a similar inhibitory effect towards human full‐length Hsp90 and the analogous bacterial HtpG. Interestingly, 17‐AAG ( 1 c ) was found to be inactive towards the bacterial chaperone.…”

Section: Introductionmentioning

confidence: 99%

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Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Mohammadi-Ostad-Kalayeh

Stahl

Scheper

et al. 2018

ChemBioChem

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Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Mohammadi-Ostad-Kalayeh

Stahl

Scheper

et al. 2018

ChemBioChem

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Biosynthetic Plasticity Enables Production of Fluorinated Aurachins

et al. 2020

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Enzyme promiscuity has important implications in the field of biocatalysis. In some cases, structural analogues of simple metabolic building blocks can be processed through entire pathways to give natural product derivatives that are not readily accessible by chemical means. In this study, we explored the plasticity of the aurachin biosynthesis pathway with regard to using fluoro‐ and chloroanthranilic acids, which are not abundant in the bacterial producers of these quinolone antibiotics. The incorporation rates of the tested precursor molecules disclosed a regiopreference for halogen substitution as well as steric limitations of enzymatic substrate tolerance. Three previously undescribed fluorinated aurachin derivatives were produced in preparative amounts by fermentation and structurally characterized. Furthermore, their antibacterial activities were evaluated in comparison to their natural congener aurachin D.

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Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Bułyszko

Dräger

Klenge

et al. 2015

Chemistry A European J

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Supplementing an AHBA(-) mutant strain of Amycolatopsis mediterranei, the rifamycin producer, with a series of benzoic acid derivatives yielded new tetraketides containing different phenyl groups. These mutasynthetic studies revealed unique reductive properties of A. mediterranei towards nitro- and azidoarenes, leading to the corresponding anilines. In selected cases, the yields of mutaproducts (fermentation products isolated after feeding bacteria with chemically prepared analogs of natural building blocks) obtained are in a range (up to 118 mg L(-1)) that renders them useful as chiral building blocks for further synthetic endeavors. The configuration of the stereogenic centers at C6 and C7 was determined to be 6R,7S for one representative tetraketide. Importantly, processing beyond the tetraketide stage is not always blocked when the formation of the bicyclic naphthalene precursor cannot occur. This was proven by formation of a bromo undecaketide, an observation that has implications regarding the evolutionary development of rifamycin biosynthesis.

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New, Non‐quinone Fluorogeldanamycin Derivatives Strongly Inhibit Hsp90

Cited by 19 publications

References 62 publications

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Biosynthetic Plasticity Enables Production of Fluorinated Aurachins

Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

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