First Total Synthesis of Tubulysin B

Pando, Orlando; Dörner, Simon; Preusentanz, Rainer; Denkert, Annika; Porzel, Andrea; Richter, Wolfgang; Wessjohann, Ludger A.

doi:10.1021/ol902320w

Cited by 65 publications

(34 citation statements)

References 21 publications

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“…All the synthetic procedures, compound characterizations and copies of 1 H, 13 C, 19 FNMR spectra and MS analyses are included in the Supporting Information.…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

“…Synthetic strategiesb ased on the coupling of the four amino acids evidenced the criticali ssue of introducing the tertiary amide-N,O-acetal on the Tuvr esidue, along with its acid and base lability. Although solutions have been proposed in this sense, [11][12][13] to our knowledge none of the published syntheses have been used to secure sufficient amountso ft ubulysins for clinicald evelopment. Alternative strategies have been focused on the production of simplified analogues by replacement of the N,O-acetal moiety with hydrogen (tubulysins Ua nd Va nd their analogues) [7,[14][15][16][17] or alkyl and ÀCH 2 ÀOÀalkyl groups.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non‐hydrolysable N‐Substituents on Tubuvaline

Sani

Lazzari²,

Folini

et al. 2017

Chemistry A European J

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Synthetic tubulysins 24 a-m, containing non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multistep synthesis. A key step was the formation of differently N-substituted Ile-Tuv fragments 10 by using an aza-Michael reaction of azido-Ile derivatives 8 with the α,β-unsaturated oxo-thiazole 5. A structure-activity relationship study using a panel of human tumour cell lines showed strong anti-proliferative activity for all compounds 24 a-m, with IC values in the sub-nanomolar range, which were distinctly lower than those of tubulysin A, vinorelbine and paclitaxel. Furthermore, 24 a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumour cell lines with acquired resistance to doxorubicin. Compounds 24 e and 24 g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24 e and 24 g interfere with tubulin polymerization in a vinca alkaloid-like manner and prevent paclitaxel-induced assembly of tubulin polymers. Both compounds exerted antimitotic activity and induced apoptosis in cancer cells at very low concentrations. Compound 24 e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, the growth of which was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.

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“…All the synthetic procedures, compound characterizations and copies of 1 H, 13 C, 19 FNMR spectra and MS analyses are included in the Supporting Information.…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non‐hydrolysable N‐Substituents on Tubuvaline

Sani

Lazzari²,

Folini

et al. 2017

Chemistry A European J

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“…Unfortunately, tubulysins are only obtained in limited amounts as fermentation, isolation procedures as well as intricate chemical synthesis are quite challenging. 14, 15, 16 Pretubulysin, a natural precursor of tubulysins, although also of minute quantity in myxobacteria, was successfully synthesized in a large-scale setup 17 and firstly tested for its bioactivity and target in some tumor cell lines. 18, 19, 20 …”

mentioning

confidence: 99%

Pretubulysin: a new option for the treatment of metastatic cancer

Braig¹,

Wiedmann²,

Liebl³

et al. 2014

Cell Death Dis

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Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCFFbw7 E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.

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“…In 2006, the Ellman group reported the first synthesis of tubulysin D, [13] and recently Wessjohann et al described the first synthesis of tubulysin B. [14] In addition, the groups of Höfle [15] and Dömling [16] patented syntheses of tubulysins. Very recently, Tamura et al reported the conversion of tubulysin D into a cyclic derivative, bridging the N terminus of Tuv with an OH group α to the thiazole ring.…”

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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First Total Synthesis of Tubulysin B

Cited by 65 publications

References 21 publications

Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non‐hydrolysable N‐Substituents on Tubuvaline

Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non‐hydrolysable N‐Substituents on Tubuvaline

Pretubulysin: a new option for the treatment of metastatic cancer

Syntheses and Evaluation of Simplified Pretubulysin Analogues

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