Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution

Erdélyi, Máté; Pfeiffer, Bernhard; Hauenstein, Kurt; Fohrer, Jörg; Gertsch, Jürg; Altmann, Karl‐Heinz; Carlomagno, Teresa

doi:10.1021/jm7013452

Cited by 53 publications

(97 citation statements)

References 44 publications

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“…[22] These findings have been reconfirmed in this study, even if the EC 50 value for 2 is somewhat higher than previously reported (Table 1). [22] In contrast, more distinct activity differences are present between 2, 3, and Epo A (1 a) at the level of cancer cell growth inhibition, with analogue 2 being clearly less active than 3 and, in particular, Epo A (1 a) ( Table 2).…”

Section: C3-modified Epothilonessupporting

confidence: 88%

“…[22] Overall, the conformation of 1 a, 2, and 3 in water closely resembled the NMR-derived structure of tubulin-bound Epo A (1 a); [21] in particular, a strong preference was observed for an antiperiplanar C1-C2-C3-C4 torsion, even in the case of 2. These findings suggested that 2 and 3 would also show similar tubulin-bound conformations as Epo A (1 a), but this hypothesis needed to be confirmed experimentally.…”

Section: Introductionsupporting

confidence: 53%

“…At the same time, experimental studies have indicated a high level of structural similarity for epothilones between the crystalline (single-crystal X-ray structure), [6] polycrystalline, [17] and solution state in organic solvents. [6,[18][19][20] The conformational preferences of Epo A (1 a) in aqueous solution partially differ from those in organic solvents; [21] importantly, they were found to include the tubulinbound conformation that was derived from solution NMR experiments with non-polymerized tubulin, [22] which is significantly populated by the free ligand in an aqueous environment. On the other hand, a distinctly different structure has been suggested for Epo A (1 a) when bound to Zn 2 + -stabilized polymeric tubulin sheets on the basis of electron crystallographic (EC) studies at intermediate resolution (2.9-4.2 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the work reported herein, we investigated the tubulin-bound conformation of a series of epothilone analogues by means of solution NMR spectroscopy, under conditions that were previously used to determine the bioactive conformation of Epo A (1 a), that is, by transferred NOE measurements of mixtures of soluble tubulin oligomers and an excess of weakly bound ligand. [22] This approach enables a direct comparison of the tubulin-bound structures of the structural analogues with that of the unmodified natural product. Following refinement by density functional theory (DFT) calculations, the structures were also docked into the tubulin binding cleft starting from the previously described orientation of bound Epo A (1 a) as derived by the INPHARMA method.…”

Section: Introductionmentioning

confidence: 99%

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The Binding Mode of Side Chain‐ and C3‐Modified Epothilones to Tubulin

et al. 2010

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The tubulin‐binding mode of C3‐ and C15‐modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin‐bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3‐modified analogues investigated. In particular, 3‐deoxy‐ (compound 2) and 3‐deoxy‐2,3‐didehydro‐Epo A (3) were found to adopt similar conformations in the tubulin‐binding cleft as Epo A, thus indicating that the 3‐OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin–epothilone complex is able to fully recapitulate the differences in tubulin‐polymerizing activity and microtubule‐binding affinity between C20‐modified epothilones 6 (C20‐propyl), 7 (C20‐butyl), and 8 (C20‐hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline‐based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of β‐His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule‐binding data for 4, 5, and Epo B.

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Section: C3-modified Epothilonessupporting

confidence: 88%

Section: Introductionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Binding Mode of Side Chain‐ and C3‐Modified Epothilones to Tubulin

et al. 2010

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“…16 A recent study showed that the 3-hydroxyl group may not be directly involved in the fundamental network of interactions between epothilones and b-tubulin. 17 This suggested that the less potent of 1 and 2, than epothilone B, may be attributed to the change of conformation of the Five new epothilone metabolites from S. cellulosum J Wang et al 16-membered macrolide framework influenced by the 3-a-D-arabinofuranoside moiety. Further work should be carried out to clarify the conformation of 1 and 2 and the structure-activity-relationship of C-3-substituted epothilones.…”

Section: Biological Activitymentioning

confidence: 99%

Five new epothilone metabolites from Sorangium cellulosum strain So0157-2

et al. 2009

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With the aim of identifying more novel natural epothilone derivatives produced by the epothilones A and B producing strain Sorangium cellulosum strain So0157-2, a large-scale fermentation (5000 l) of the strain was carried out. As a result, five new epothilone variants (1-5) were isolated from the fermentation broth. Their structures were established as 3-a-Darabinofuranosides of epothilones A (1), B (2), D (3), C 9 (4) and 8-demethyl epothilone A (5) by extensive NMR analysis and chemical methods. Bioassay results showed that compounds 1 and 2 had a weaker cytotoxic activity than did epothilone B. Keywords: cytotoxic activity; epothilone derivatives; Sorangium cellulosum INTRODUCTION Epothilones are naturally occurring 16-membered ring macrolides that constitute a novel class of antimicrotubule-targeting agents. As the major products, epothilones A and B, were originally isolated from fermentations of the soil-derived myxobacterium Sorangium cellulosum So ce90, 1-3 many natural epothilone analogs and related structures have been described. [4][5][6] Moreover, synthetic and semisynthetic methods were important alternatives for obtaining epothilone analogs. At present, more epothilone variants are prepared in a synthetic manner. 7,8 Of all the epothilones and other variants coming from natural resources and synthesis, ixabepilones have been approved by FDA in 2007 for clinical use for the treatment of certain forms of breast cancer, in addition to a number of them being in preclinical and clinical trials. 9 The attractive potential of epothilones led us to search for more potent and selective epothilone derivatives to satisfy the needs of chemotherapy for tumors. Presumably, when fermentation was scaled up, there were some minor and new analogs that were not isolated in small-scale fermentation. Hence, we investigated the chemical compositions of large-scale fermentation (5000 l) of epothilones A and B producing strain S. cellulosum strain So0157-2, 10 and five new epothilone variants (1-5, Figures 1 and 2) were obtained. Their structures were established as 3-a-D-arabinofuranosides of epothilones A (1), B (2), D (3), C 9 (4) and 8-demethyl epothilone A (5) by extensive NMR analysis and chemical methods. This paper describes the isolation and structure determination of the five new compounds and the cytotoxic activity of compounds 1 and 2.

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Chemistry and Biology of Epothilones

Altmann

Schinzer

2014

Methods and Principles in Medicinal Chemistry

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Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution

Cited by 53 publications

References 44 publications

The Binding Mode of Side Chain‐ and C3‐Modified Epothilones to Tubulin

The Binding Mode of Side Chain‐ and C3‐Modified Epothilones to Tubulin

Five new epothilone metabolites from Sorangium cellulosum strain So0157-2

Chemistry and Biology of Epothilones

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