Archazolid A-15-O-β-<scp>d</scp>-glucopyranoside and iso-Archazolid B: Potent V-ATPase Inhibitory Polyketides from the Myxobacteria Cystobacter violaceus and Archangium gephyra

Horstmann, Nicole; Essig, Sebastian; Bockelmann, Svenja; Wieczorek, Helmut; Huss, Markus; Sasse, Florenz; Menche, Dirk

doi:10.1021/np200036v

Cited by 29 publications

(32 citation statements)

References 36 publications

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“…30). Recently, Menche and co-workers investigated both V-ATPase inhibition and the antiproliferative effect of archazolid derivatives and hypothesized that additional targets might be involved in their antitumour potential because of the much more pronounced antiproliferative activity, especially for derivatives with weaker V-ATPase inhibition 31 . Clear target identification may also enable the recognition and avoidance of unwanted side effects of future archazolid-derived chemotherapies and inform chemical scaffold modification for other indications.…”

Section: Resultsmentioning

confidence: 99%

Revealing the macromolecular targets of complex natural products

Reker¹,

Perna²,

Rodrigues³

et al. 2014

Nature Chem

120

102

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Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.

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Section: Resultsmentioning

confidence: 99%

Revealing the macromolecular targets of complex natural products

Reker¹,

Perna²,

Rodrigues³

et al. 2014

Nature Chem

120

102

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“…Archazolids potently inhibit V-ATPase activity (IC 50 : nanomolar range) exerting little or no effects on Na þ /K þ -ATPases and mitochondrial F-ATPases (8). To date, archazolid A, B, and F have been isolated from their natural producer and archazolid A and B have also been successfully chemically synthesized (9,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

The V-ATPase-Inhibitor Archazolid Abrogates Tumor Metastasis via Inhibition of Endocytic Activation of the Rho-GTPase Rac1

et al. 2012

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The abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination. Cancer Res; 72(22); 5976-87. Ó2012 AACR.

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“…(S233) that exhibit anticancer activity constitute watersoluble compounds and are unlikely to be previously described tubulysins. Horstmann et al (2011) reported inhibition of cervix and prostate cancer cell lines by secondary metabolites of Cystobacter sp. and Archangium sp.…”

Section: Discussionmentioning

confidence: 99%

Molecular and functional characterization of myxobacteria isolated from soil in India

et al. 2017

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This study reports the isolation of myxobacteria from soil collected from plains in north India. Based on the morphology and 16S rDNA sequence, the isolated myxobacteria were identified as Corallococcus sp., Pyxidicoccus sp., Myxococcus sp., Cystobacter sp. and Archangium sp. The myxobacteria were functionally characterized to assess their ability to produce antibacterial and anticancer metabolites. The isolates were found to be functionally versatile as they produced extracellular bioactive molecules that exhibited high frequency of activities against Bacillus cereus, Mycobacterium smegmatis, Enterobacter cloacae and Pseudomonas syringae. The strains also showed cytotoxic activity against the human cancer cell lines of liver, pancreas, prostrate, bone and cervix. These results indicate the importance of isolating diverse strains of myxobacteria from unexplored habitats to find novel bioactive compounds. Moreover, the bioactive molecules explored in this study are predominantly hydrophilic compounds, obviating the limitations of solubility-related aspect of drug discovery.

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Archazolid A-15-O-β-d-glucopyranoside and iso-Archazolid B: Potent V-ATPase Inhibitory Polyketides from the Myxobacteria Cystobacter violaceus and Archangium gephyra

Abstract: CitationArchazolid A-15-O--D-glucopyranoside and iso-archazolid B: potent V-ATPase inhibitory polyketides from the myxobacteria Cystobacter violaceus and Archangium

Cited by 29 publications

References 36 publications

Revealing the macromolecular targets of complex natural products

Revealing the macromolecular targets of complex natural products

The V-ATPase-Inhibitor Archazolid Abrogates Tumor Metastasis via Inhibition of Endocytic Activation of the Rho-GTPase Rac1

Molecular and functional characterization of myxobacteria isolated from soil in India

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