Entwicklung struktureller Template zur Mikrotubulihemmung durch weitgehende Abwandlung der Epothilon‐Grundstruktur

Cachoux, Frédéric; Isarno, Thomas; Wartmann, Markus; Altmann, Karl‐Heinz

doi:10.1002/ange.200501760

Cited by 16 publications

(23 citation statements)

References 31 publications

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“…In the EC-derived model, the presence of a critical hydrogen bond between the 3OH group and the T274 residue is not reconcilable with the high activity of (E)-3-deoxy-2,3-didehydroepothilones, which lack the hydroxyl group, or of 3-deoxyepothilones, which lack both the hydroxyl group and the structural constrainment of the additional double bond. [25] Additionally, we observe that the hydrophilic carbonyl and hydroxyl groups at C1' and C2' of PTX, respectively, are placed in a similar position to the 3OH group of EpoA, without any evident contacts with tubulin ( Figure 2). [19] The positively charged side chain of the R282 residue entertains extensive electrostatic contacts with the polar 7OH group of EpoA (Figure 3).…”

Section: +mentioning

confidence: 89%

Structural Basis of the Activity of the Microtubule‐Stabilizing Agent Epothilone A Studied by NMR Spectroscopy in Solution

et al. 2007

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Section: +mentioning

confidence: 89%

Structural Basis of the Activity of the Microtubule‐Stabilizing Agent Epothilone A Studied by NMR Spectroscopy in Solution

et al. 2007

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“…These studies revealed that the potency-enhancing effect of the dimethylbenzimidazole moiety is rather general in nature and extends to the corresponding analogues of Epo A and C, [162] of 3-deoxyEpo B (105), and also of trans-Epo A (106) and its 3-deoxy derivative (107). [149] For example, compound 106 is essentially equipotent to Epo B (which is the most potent natural epothilone) against drug-sensitive human cancer cell lines (IC 50 values against the human cervix carcinoma cell line KB-31 are 0.25 nm and 0.29 nm for 106 and Epo B, respectively). Likewise, the modification can almost completely compensate for the loss in cellular potency caused by removal of the 3-hydroxy function in Epo B (compound 105: IC 50 (KB-31) = 0.58 nm versus 0.29 nm for Epo B).…”

Section: Side Chain Modificationsmentioning

confidence: 98%

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

et al. 2007

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Epothilones have captured the attention of chemists, biologists, and drug researchers ever since they were found to inhibit human cancer cell growth through a “taxol‐like” mechanism over ten years ago. Today, at least seven epothilone‐derived agents have entered clinical trials. However, additional new and exciting analogues have emerged in recent years, suggesting that the potential of these natural products to serve as leads for new anticancer drugs is far from exhausted.

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“…As a consequence, removal of this group was predicted to have only a limited effect on the binding energy and on cellular potency, in agreement with the available experimental data on 3-deoxy-Epo, such as 27. [15][16][17] In contrast, in the EC model [5] this group was proposed to stabilize the binding of Epo A by establishing direct hydrogen-bond interactions with Thr 274 (see Figure 3 c).…”

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confidence: 89%

“…[3a] Moreover, both the model and the NMR structure showed that the 3-OH group was not involved in any direct interaction with the protein, thus suggesting it is not essential for activity, in agreement with additional experimental data. [15][16][17] The theoretical model also suggested the C1 carbonyl oxygen forms part of a hydrogen bond with Gly 368 and mimics the C2' hydroxy group of the NMR PTX structure. In the NMR structure, this group was too far from any protein hydrogen-bond donor to form a direct hydrogen bond, but NMR study suggested [7] that interactions between the C1 carbonyl group and the protein were likely to be mediated by a water bridge.…”

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confidence: 92%

Evaluation of Novel Epothilone Analogues by means of a Common Pharmacophore and a QSAR Pseudoreceptor Model for Taxanes and Epothilones

et al. 2009

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Taxanes (TX) and epothilones (Epo) comprise the most prominent classes of microtubule-stabilizing antimitotic agents (MSAA), which include three compounds currently in clinical use for the treatment of cancer: paclitaxel (PTX, Taxol), docetaxel (Taxotere), and the Epo B lactam ixabepilone (Ixempra). In spite of the clinical importance of these agents, the binding mode of either TX or Epo to their target protein (b-tubulin) has yet to be resolved. The interactions of taxanes (TX) and epothilones (Epo) with the tubulin/microtubule system was initially assumed to involve a common pharmacophore for both classes of compounds.[1] While this hypothesis was subsequently challenged on the basis of electron crystallography studies on a complex between tubulin polymer sheets and Epo A, the idea of a common pharmacophore for taxanes and epothilones was recently revived by results of solution NMR studies. [7] Here, we describe the application of a 3D QSAR pseudoreceptor model, previously developed on the basis of the common pharmacophoric hypothesis, to a set of new Epo derivatives recently reported in the literature. Despite the structural differences between the molecules originally employed to build the model and the new set of analogues investigated here, predicted activities were in excellent agreement with experimental data. Moreover, the pharmacophore of Epo was found to be in agreement with the binding mode of Epo A with tubulin recently proposed on the basis of NMR studies. In fact, three out of four common pharmacophoric points between TX and Epo were satisfied by the model, thus further supporting the common pharmacophore hypothesis.The PTX-complexed tubulin structure [2] was used to propose different binding models of Epo into the PTX binding site. [3] Amongst others, we have put forward the hypothesis of a common pharmacophoric model [4] on the basis of which a 3D QSAR pseudoreceptor model was built. Binding of Epo and TX to this model gave very promising results; predicted activity and interactions were in good agreement with both experimental activity trends and mutagenesis studies. In 2004, the structure of epothilone A (1, Figure 1) bound to the electron crystallography (EC) structure of tubulin, was proposed, [5] questioning the hypothesis of a common binding mode for the two classes of tubulin modulators. However, this structural model was not able to rationalize all the biological data available at that time and attempts to use the EC-derived bioactive conformation of 1 for the design of conformationally restricted derivatives of 1 was unsuccessful, thus prompting Snyder and co-workers to re-examine their Epo-tubulin binding representation.[6] Finally, Carlomagno and co-workers [7] reported the results of a solution NMR study on a complex between nonpolymerized tubulin (i.e., tubulin in an undefined, soluble, oligomeric state) and 1. Intriguingly, the binding mode of 1 with tubulin, as derived from the NMR data, was in good agreement with our theoretical model. The different binding modes proposed by ...

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Entwicklung struktureller Template zur Mikrotubulihemmung durch weitgehende Abwandlung der Epothilon‐Grundstruktur

Cited by 16 publications

References 31 publications

Structural Basis of the Activity of the Microtubule‐Stabilizing Agent Epothilone A Studied by NMR Spectroscopy in Solution

Structural Basis of the Activity of the Microtubule‐Stabilizing Agent Epothilone A Studied by NMR Spectroscopy in Solution

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

Evaluation of Novel Epothilone Analogues by means of a Common Pharmacophore and a QSAR Pseudoreceptor Model for Taxanes and Epothilones

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