Total Synthesis of Hypermodified Epothilone Analogs with Potent in Vitro Antitumor Activity

Kuzniewski, Christian N.; Gertsch, Jürg; Wartmann, Markus; Altmann, Karl‐Heinz

doi:10.1021/ol800089x

Cited by 29 publications

(31 citation statements)

References 20 publications

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“…CK246 was kindly provided by Professor Karl-Heinz Altmann (Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich Switzerland) (12). Velcade was kindly provided by Prof. Bjørn Tore Gjertsen, Haukeland University Hospital, Norway (13).…”

Section: Compoundsmentioning

confidence: 99%

“…Images were acquired for every third day as 53 5 montages with a 310 objective and quantified with the parameter tube total length (BD Attovision software). Once the network is formed at day 3, this parameter reflects the stability of the network (day [3][4][5][6][7][8][9][10][11][12], and inhibition of network formation due to drug treatment can be measured. (b) Images from a developing network acquired every third day during a 12-day period showing fluorescent EC (gray).…”

Section: Ic 50 Calculationsmentioning

confidence: 99%

“…To evaluate consistency in screening hit identification, a double-blinded pilot screen was conducted using a prearrayed compound plate comprising randomly distributed small molecule VEGFR2 tyrosine kinase inhibitors, PTK787/ ZK (200 nM and 50 nM) and CHIR258 (200 nM and 50 nM), and two vascular disruptive agents, combretastatin CA-4 (100 nM and 20 nM) (17)(18)(19), an inhibitor of microtubule polymerization, and CK246 (100 nM and 20 nM), an epothilone analog functioning as a microtubule stabilizer (12), among DMSO control wells. Two 96-well plates seeded with EC-vSMC co-cultures were treated with the compound plate that also contained nine DMSO controls for calculation of a threshold value (Fig.…”

Section: Proof Of Principle: High-throughput Screeningmentioning

confidence: 99%

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A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

et al. 2009

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The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, highthroughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGFswitch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot highthroughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High-throughput screening using the EC-vSMC co-culture assay establishes a new platform to screen for novel anti-angiogenic compounds for cancer therapy. ' 2009 International Society for Advancement of Cytometry Key termshigh-throughput screening; endothelial/mural cell co-culture; angiogenesis INHIBITING angiogenesis is a validated therapeutic modality for cancer (1). Hence, new agents that potently inhibit pathological angiogenesis are a critical component of future combination cancer therapies (2). The identification of candidate therapeutics relies on current in vitro angiogenesis assays that measure effects on endothelial cell migration, proliferation, apoptosis and tube formation, and in vivo models such as the chick chorioallantoic membrane assay, corneal neovascularization assay, and Matrigel plug assays (3-5). Current in vitro angiogenesis assays are generally focused on specific behaviors of monocultured endothelial cells (EC) (e.g., migration, proliferation) and fail to model heterotypic perivascular interactions, whereas in vivo systems are not compatible ...

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Section: Compoundsmentioning

confidence: 99%

Section: Ic 50 Calculationsmentioning

confidence: 99%

Section: Proof Of Principle: High-throughput Screeningmentioning

confidence: 99%

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A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

et al. 2009

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“…Not surprisingly, their unusual structural/chemical properties and interesting bonding characteristics have attracted the attention of physical organic chemists . Despite their strained structures and high reactivity, cyclopropanes are usually quite stable at room temperature, and are present in a variety of natural and unnatural products including pheromones, terpenes, fatty acid metabolites and epothilone analogs …”

Section: Introductionmentioning

confidence: 99%

Tandem catalytic enantio‐ and diastereoselective synthesis of cyclopropyl alcohols using aryl aldehydes

Kim

Walsh

2012

J of Physical Organic Chem

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The prevalence of cyclopropanes in biologically active compounds has fueled many investigations into their preparation. Despite significant advances, more efficient methods for their catalytic enantioselective synthesis remain in demand. Previously, we reported a novel tandem approach to diastereo‐ and enantioenriched cyclopropyl alcohols. Our method involved an initial asymmetric C–C bond formation by addition of organozinc reagents to aldehydes catalyzed by a (−)‐MIB‐based catalyst. The resulting allylic zinc alkoxides were then subject to directed cyclopropanations. Although this approach provided cyclopropyl alcohols with very high enantio‐ and diastereoselectivity, it was successful with only aliphatic aldehydes. Aryl aldehyde substrates, on the other hand, exhibited low conversion and variable diastereomeric ratios. The present study is aimed at raising the stereoselectivity and yield of the aforementioned tandem reaction with aryl aldehyde substrates to make the method synthetically useful. Herein, we report the successful optimization of aryl aldehyde substrates in our one‐pot tandem approach leading to cyclopropyl alcohols with high yields and enantio‐ and diastereoselectivities. Copyright © 2012 John Wiley & Sons, Ltd.

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“…The fluoro-group was displaced by nucleophilic aromatic substitution, thus allowing facile incorporation of the amine function at C4. [9] The acid moiety was readily transformed into Scheme 1. Structures of SR1 and compounds identified in the primary screen that expand phenotypic HSCs (SR2-5).…”

mentioning

confidence: 99%

Small‐Molecule Regulators of Human Stem Cell Self‐Renewal

et al. 2011

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Total Synthesis of Hypermodified Epothilone Analogs with Potent in Vitro Antitumor Activity

Cited by 29 publications

References 20 publications

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

Tandem catalytic enantio‐ and diastereoselective synthesis of cyclopropyl alcohols using aryl aldehydes

Small‐Molecule Regulators of Human Stem Cell Self‐Renewal

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