The Structure and Cytocidal Activity of Herbimycin C

Shibata, Kiyoshi; Satsumabayashi, Sadayoshi; Nakagawa, Akira; Ōmura, Satoshi

doi:10.7164/antibiotics.39.1630

Cited by 25 publications

(11 citation statements)

References 5 publications

(1 reference statement)

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“…[1][2][3] Geldanamycin competes with ATP at the nucleotide binding site in the N-terminal domain of heat shock protein 90 (Hsp90), and thereby acts as a Hsp90 inhibitor. [4][5][6] Hsp90 is a molecular chaperone the main function of which is to ensure the stability and proper folding of its client proteins.…”

Section: Introductionmentioning

confidence: 99%

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

et al. 2009

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Tailor made: We report the rational biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound. A rational biosynthetic engineering approach was applied to the optimization of the pharmacological properties of the benzoquinone ansamycin, geldanamycin. Geldanamycin and its natural or semisynthetic derivatives have the potential to serve as anticancer chemotherapeutic agents. However, these first-generation Hsp90 inhibitors share an unfavorable structural feature that causes both reduced efficacy and toxicity during clinical evaluation. We report the rationally designed biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. A 15-hydroxyl-17-demethoxy non-quinone analogue, DHQ3, exhibited stronger inhibition of Hsp90 ATPase activity (4.6-fold) than geldanamycin. Taken together, the results of the present study indicate that rational biosynthetic engineering allows the generation of derivatives of geldanamycin with superior pharmacological properties.

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Section: Introductionmentioning

confidence: 99%

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

et al. 2009

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“…Among these compounds, calphostin C (110) showed highest potency. 8.16; 126-128) [112][113][114][115][116], clavilactones A-E (129)(130)(131)(132)(133) [117,118], F-12509A (134) [119,120], stemphone (135), and cochlioquinone A (136) [121][122][123]. 8.15-17; 118-125) [106][107][108][109][110][111], herbimycins A-C (Fig.…”

Section: Benzoquinones (Table 83)mentioning

confidence: 99%

Protein Kinase Inhibitors from Microorganisms

Radhika

Kumar

Nagasree

2015

Studies in Natural Products Chemistry

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“…Although too toxic to be developed as an anticancer drug, its optimization by semisynthesis resulted in two promising derivatives: 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG) and 17‐(2‐dimethylamino)ethylamino‐17‐demethoxygeldanamycin (17‐DMAG), which are more bioavailable than geldanamycin . The concern regarding the toxicity of geldanamycin analogs due to their redox‐active quinone moiety led to the discovery of similar pharmacophoric compounds, such as macbecins and herbimycins with potent anticancer activity, which are presently under clinical trial. Radicicol (RAD), an antibiotic obtained from Chaetomium chiversii , is the most potent inhibitor of Hsp90 in vitro, but the reactivity of its epoxide group and the sensitivity of its conjugated double bonds to Michael additions render it inactive in vivo .…”

Section: Introductionmentioning

confidence: 99%

Discovery of N‐pyridoyl‐Δ²‐pyrazolines as Hsp90 inhibitors

Kadasi

Yerroju

Gaddam

et al. 2019

Archiv der Pharmazie

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Hsp90, as a key molecular chaperone, plays an important role in modulating the activity of many cell signaling proteins and is an attractive target for anticancer therapeutics.Herein, we report the discovery of N-pyridoyl-Δ 2 -pyrazoline analogs as novel Hsp90 inhibitors by integrated approaches of drug design, organic synthesis, cell biology, and qualitative proteomic analysis. Novel chemical compounds were designed and optimized in the adenosine triphosphate-binding site of Hsp90; lead optimized compounds were found to have significant interactions with Asp93 and other amino acids crucial for Hsp90 inhibition. The designed compounds were synthesized by a two-step procedure; different aromatic aldehydes were reacted with various acetophenones to form substituted 1,3-diphenyl-prop-2-enones (Ic-Io), which upon reaction with isonicotinic acid hydrazide in the presence of glacial acetic acid form N-pyridoyl-Δ 2 -pyrazoline compounds (PY1-PY13). Compounds PY3, PY2, and PY1 were identified as potential leads amongst the series, with promising anticancer activity against human breast cancer and melanoma cells, and the ability to inhibit Hsp90 similar to radicicol by drug-affinity responsive target stability proteomic analysis in a whole-cell assay.

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The Structure and Cytocidal Activity of Herbimycin C

Cited by 25 publications

References 5 publications

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

Protein Kinase Inhibitors from Microorganisms

Discovery of N‐pyridoyl‐Δ²‐pyrazolines as Hsp90 inhibitors

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The Structure and Cytocidal Activity of Herbimycin C

Cited by 25 publications

References 5 publications

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

Protein Kinase Inhibitors from Microorganisms

Discovery of N‐pyridoyl‐Δ2‐pyrazolines as Hsp90 inhibitors

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Discovery of N‐pyridoyl‐Δ²‐pyrazolines as Hsp90 inhibitors