Synthesis and Biological Evaluation of Pretubulysin and Derivatives

Ullrich, Angelika; Herrmann, Jennifer; Müller, Rolf; Kazmaier, Uli

doi:10.1002/ejoc.200900999

Cited by 71 publications

(63 citation statements)

References 29 publications

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“…Pretubulysin was active in a low to sub-nanomolar range against various tumor cell lines [24], [27]. Thus, based on the GI 50 values, pretubulysin is, on average, only a factor of 10 or 100 less active than naturally occurring tubulysin A or D, respectively.…”

Section: Resultsmentioning

confidence: 98%

“…Because of the lack of this structural moiety in pretubulysin, we are now able to synthetically produce pretubulysin D in multigram quantities and thus, circumvent the supply issues typical of most natural products in preclinical development. Although pretubulysin lacks the N,O-acetal and acetoxy functionalities of Tuv, these moieties do not appear to be crucial for biological activity, as determined by growth inhibition of cancer cell lines [24], [27]…”

Section: Introductionmentioning

confidence: 99%

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Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Herrmann

Elnakady

Wiedmann³

et al. 2012

PLoS ONE

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Pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Herrmann

Elnakady

Wiedmann³

et al. 2012

PLoS ONE

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“…In the case of other myxobacterial compounds, for example, tubulysins, a high tolerance for simplification of the core structure without dramatic loss of activity was observed in SAR studies. [27][28][29] Roimatacene (1) is a new antimicrobial secondary metabolite from myxobacteria inhibiting selectively the growth of Gram-negative bacteria. The biological activity against P. stutzeri is of particular interest, because infections with multidrug resistant (!…”

Section: Resultsmentioning

confidence: 99%

Roimatacene: An Antibiotic against Gram‐Negative Bacteria Isolated from Cystobacter ferrugineus Cb G35 (Myxobacteria)

Zander

Gerth

Mohr

et al. 2011

Chemistry A European J

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Roimatacene (1) was isolated from the myxobacterium Cystobacter ferrugineus strain Cb G35 in a bioactivity-guided process, by following the antimicrobial activity against Escherichia coli. Since 1 was extremely sensitive to oxygen, a protective isolation and handling protocol was developed, by utilizing the free radical scavenger 4-ethoxyphenol. The structure of 1 was determined by HRMS, 1D and 2D NMR spectroscopy and chemical derivatization to acetonides and Mosher esters to finally establish the absolute configuration. Methionine and acetate were identified as building blocks in the biosynthesis of 1 by feeding experiments with differently (13)C-labeled precursors. The antimicrobial activity of 1 was determined in a broad screening revealing 1 to inhibit several Gram-negative bacteria.

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“…[23] Whereas the tubulysins and pretubulysins showed IC 50 values in the sub-nanomolar range, phenylanalogue 1 was two magnitudes of order less potent (ca. 100 nm).…”

Section: Introductionmentioning

confidence: 99%

Syntheses and Evaluation of Simplified Pretubulysin Analogues

2011

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The syntheses of new tubulysin analogues are described, in which the central amino acid, tubuvaline, is replaced by the rather simple building blocks phenyltubuvaline and phenoxytubuvaline. These analogues can be obtained in only two to three steps from easily accessible starting materials. Although the new derivatives are less active than the tubulysins, their activities towards U‐2 OS tumor cells are still in the nanomolar range.

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Synthesis and Biological Evaluation of Pretubulysin and Derivatives

Cited by 71 publications

References 29 publications

Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Roimatacene: An Antibiotic against Gram‐Negative Bacteria Isolated from Cystobacter ferrugineus Cb G35 (Myxobacteria)

Syntheses and Evaluation of Simplified Pretubulysin Analogues

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