Total Synthesis of the Tubulin Inhibitor WF‐1360F Based on Macrocycle Formation through Ring‐Closing Alkyne Metathesis

Neuhaus, Christian; Liniger, Marc; Stieger, Martin; Altmann, Karl‐Heinz

doi:10.1002/anie.201300576

Cited by 70 publications

(36 citation statements)

References 46 publications

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“…We initially sought to investigate the molecular mechanism of action of rhizoxin. To provide insight into the binding mode of rhizoxin with tubulin, we soaked crystals of a protein complex composed of two αβ-tubulin (T 2 ), the stathmin-like protein RB3 (R), and tubulin tyrosine ligase (TTL; the complex is denoted T 2 R-TTL) (17,18) with the natural rhizoxin variant 2,3-desepoxy rhizoxin (19) [referred to as "rhizoxin F" from here on (20); Fig. 1A] and determined its tubulin-bound structure by X-ray crystallography at 2.0-Å resolution (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

Prota

Bargsten

Dı́az

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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241

227

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The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubuledestabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubuledestabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.drug mechanism | microtubule-targeting agents | X-ray crystallography

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Section: Resultsmentioning

confidence: 99%

“…17, 18, and 30. The synthesis of 2,3-desepoxy rhizoxin and PM060184 has been described elsewhere (13,19). Maytansine was obtained from the National Institutes of Health Open Chemical Repository Collection.…”

Section: Methodsmentioning

confidence: 99%

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

Prota

Bargsten

Dı́az

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

241

227

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“…In some cases,the imido complexes were best isolated after exchange of the nitrile by pyridine; alternatively,t he crude material was hydrolyzed and the amount of the released aniline 12 and 4-methoxybenzonitrile (13)determined. [25][26][27] Although the metathesis of alkynes has gained considerable momentum in recent years, [12,28] not least because of the excellent application profile of 2 and relatives,t he reactions typically require ambient temperature or higher. Although no single crystals of the expected imido complex 14 have been obtained so far (it lacks the stabilizing nitrile present in 9b), the high yield of the corresponding aniline 12 b after hydrolytic work up leaves no doubt that am etathetic cleavage of the substrate must have taken place.…”

Section: Methodsmentioning

confidence: 99%

The Triple‐Bond Metathesis of Aryldiazonium Salts: A Prospect for Dinitrogen Cleavage

Lackner

Fürstner

2015

Angew Chem Int Ed

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The {N₂} unit of aryldiazonium salts undergoes unusually facile triple-bond metathesis on treatment with molybdenum or tungsten alkylidyne ate complexes endowed with triphenylsilanolate ligands. The reaction transforms the alkylidyne unit into a nitrile and the aryldiazonium entity into an imido ligand on the metal center, as unambiguously confirmed by X-ray structure analysis of two representative examples. A tungsten nitride ate complex is shown to react analogously. Since the bonding situation of an aryldiazonium salt is similar to that of metal complexes with end-on-bound dinitrogen, in which {N₂}→M σ donation is dominant and electron back donation minimal, the metathesis described herein is thought to be a conceptually novel strategy toward dinitrogen cleavage devoid of any redox steps and, therefore, orthogonal to the established methods

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“…Furthermore, Altmann and co-workers reported the synthesis of WF-1360F, a close relative of rhizoxin endowed with potent tubulin polymerization inhibitory activity (Table 1, Entry 25). 85 While enyne 105 was readily prepared by RCAM, 3,90 the subsequent semi-reduction proved challenging. Various attempts at transition-metal-catalyzed hydrogenation, hydrostannation, hydroboration, and hydrozirconation of the triple bond essentially met with failure; only the transhydrosilylation with (EtO) 3 SiH catalyzed by [CpRu(MeCN) 3 ]-PF 6 was successful but afforded the desired (E,E)-diene 106 after protodesilylation in low and difficult-to-reproduce yields (3040%, over 2 steps) and unsatisfactory selectivity (E:Z 1:4.7 to 1:2.6).…”

Section: 92mentioning

confidence: 99%

“…Therefore the authors resorted to an in situ reductive decomplexation of the corresponding acetylenehexacarbonyl dicobalt complex with ethylpiperidine hypophosphite, followed by a Z/Eisomerization with AIBN/PhSH. 85 Not only ruthenium-based trans-hydrosilylations have been used in the context of natural product synthesis. A promising example invoking an iron catalyst was reported by Belger and Plietker.…”

Section: 92mentioning

confidence: 99%

Progress in the trans-Reduction and trans-Hydrometalation of Internal Alkynes. Applications to Natural Product Synthesis

Frihed

Fürstner

2016

Bulletin of the Chemical Society of Japan

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The classical repertoire of synthetic organic chemistry is short of methods that allow triple bonds to be transformed into (E)-alkenes with high selectivity in the presence of other reducible sites. Recent advances, most notably in ruthenium-catalyzed trans-hydrogenation, trans-hydrosilylation, trans-hydrogermylation, trans-hydrostannation, and even trans-hydroboration hold the promise of filling this gap. This review illustrates the state-of-the-art in the field by summarizing applications of these emerging methodologies to natural product synthesis. A comparison of ruthenium-catalyzed and radical-induced trans-hydrostannations provides further insights into the application profile of these transformations

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Total Synthesis of the Tubulin Inhibitor WF‐1360F Based on Macrocycle Formation through Ring‐Closing Alkyne Metathesis

Cited by 70 publications

References 46 publications

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

The Triple‐Bond Metathesis of Aryldiazonium Salts: A Prospect for Dinitrogen Cleavage

Progress in the trans-Reduction and trans-Hydrometalation of Internal Alkynes. Applications to Natural Product Synthesis

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