A Natural Product Inspired Tetrahydropyran Collection Yields Mitosis Modulators that Synergistically Target CSE1L and Tubulin

Voigt, Tobias; Gerding-Reimers, Claas; Tran, Tuyen Thi Ngoc; Bergmann, Sabrina; Lachance, Hugo; Schölermann, Beate; Brockmeyer, Andreas; Janning, Petra; Ziegler, Slava; Waldmann, Herbert

doi:10.1002/ange.201205728

Cited by 29 publications

(33 citation statements)

References 39 publications

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“…Nonetheless, background proteins need to be considered for every probe since putative unspecific binders could prove to be the physiological target of the compound of interest (e.g. Tubulexin, Table 1, entry 11, see Section 5.5) 62…”

Section: Approaches To Target Identificationmentioning

confidence: 99%

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

et al. 2013

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Identification and confirmation of bioactive small-molecule targets is a crucial, often decisive step both in academic and pharmaceutical research. Through the development and availability of several new experimental techniques, target identification is, in principle, feasible, and the number of successful examples steadily grows. However, a generic methodology that can successfully be applied in the majority of the cases has not yet been established. Herein we summarize current methods for target identification of small molecules, primarily for a chemistry audience but also the biological community, for example, the chemist or biologist attempting to identify the target of a given bioactive compound. We describe the most frequently employed experimental approaches for target identification and provide several representative examples illustrating the state-of-the-art. Among the techniques currently available, protein affinity isolation using suitable small-molecule probes (pulldown) and subsequent mass spectrometric analysis of the isolated proteins appears to be most powerful and most frequently applied. To provide guidance for rapid entry into the field and based on our own experience we propose a typical workflow for target identification, which centers on the application of chemical proteomics as the key step to generate hypotheses for potential target proteins.

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Section: Approaches To Target Identificationmentioning

confidence: 99%

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

et al. 2013

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“…One benefit of this approach in comparison with ICAT and ITRAQ is that the labeling takes place at the protein level early in the workflow, conferring higher consistency and accuracy. This strategy has been successfully applied to the target ID of several bioactive small molecules (Raj et al 2011;Wen et al 2012;Voigt et al 2013;Kronke et al 2014).…”

Section: Quantitative Proteomics Approachmentioning

confidence: 98%

Affinity purification in target identification: the specificity challenge

Zheng

2015

Arch. Pharm. Res.

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Since phenotype-based screening directly evaluates capability of small molecules for modulating biology in actual biological systems, it has become an important discover modality in modern pharmaceutical sciences. However, in order to fully elucidate the molecular mechanism underlying the bioactivity of small molecules, identification of their biological targets is an indispensable step. Among the many target identification strategies developed during the past several decades, affinity purification remains to be one of the most important and powerful approaches, as it can directly reveal the physical interactions between small molecules and their biomolecular targets. However, due to the complexity of the proteome and the diversity of small molecule-protein interactions, affinity purification faces the specificity challenge: how to identify the true specific targets from the non-specific background? Focusing on this challenge, in this review, we briefly introduce the history and background of affinity purification, and then we discussed the major technological developments aiming to address this challenge. We have summarized these approaches in two categories: noise reduction and comparative distinction. This review also highlights the importance of choosing an integrated approach combining multiple methods to achieving success in target identification.

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“…Often natural products exhibit polypharmacological activity, targeting several pathways relevant20 for cancer pathogenesis 21. 22 The principle of addressing multiple targets by natural products can be transferred to synthetic multitarget ligands 23. In this study, we intended to discover chemical compounds exhibiting cytotoxic profiles and simultaneously targeting sEH.…”

Section: Ic50 Values Of Synthesized (E)‐styryl‐1h‐benzo[d]imidazoles[a]mentioning

confidence: 99%

Jatrophane Diterpenes: Preparation of the Western Fragment of Pl‐3

et al. 2014

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Jatrophane diterpenes are structurally intriguing natural products with promising biological properties. Herein, the synthesis of the western fragment of the Euphorbiaceae constituent Pl‐3 starting from (1R,5S)‐bicyclo[3.2.0]hept‐2‐en‐6‐one is described. Key steps in the sequence include a Baeyer–Villiger oxidation, an iodolactonization reaction, and the installation of the northern side chain through the addition of a lithiated vinyl bromide. The overall efficiency of the route is increased by taking advantage of latent symmetry.

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A Natural Product Inspired Tetrahydropyran Collection Yields Mitosis Modulators that Synergistically Target CSE1L and Tubulin

Cited by 29 publications

References 39 publications

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Affinity purification in target identification: the specificity challenge

Jatrophane Diterpenes: Preparation of the Western Fragment of Pl‐3

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