Oxidative Approach Enables Efficient Access to Cyclic Azobenzenes

Maier, Martin S.; Hüll, Katharina; Reynders, Martin; Matsuura, Bryan S.; Leippe, Philipp; Ko, Tongil; Schäffer, Lukas; Trauner, Dirk

doi:10.1021/jacs.9b08794

Cited by 71 publications

(81 citation statements)

References 65 publications

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“…The reduction to the corresponding amino compounds (i.e., 42 ) succeeded with tin(II) chloride in refluxing ethyl acetate, whereas a standard hydrogenation using palladium catalyst resulted in dehalogenation. For the ring closure to the diazocine 43 , we used meta -chloroperoxybenzoic acid in acetic acid as reported by the Trauner group recently [ 45 ]. The stannylation of diazocine 44 and subsequent cross-coupling with building block 24 proceeded as described above.…”

Section: Resultsmentioning

confidence: 99%

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Heintze

Schmidt

Rodat

et al. 2020

IJMS

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In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

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Section: Resultsmentioning

confidence: 99%

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Heintze

Schmidt

Rodat

et al. 2020

IJMS

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“…These targets may be located both cytosolically, as well as in water-excluded environments where the PHT scaffold may be even more advantageously applicable. In general, novel photoswitches that can be used to access new photochemical performance without requiring conceptual redesign to retain on-target bioactivity (such as spectrally shifted diazocines, 42,43 tetra-ortho-substituted azobenzenes 12,44 and azoniums 45 ) are recognised as high-value targets in photopharmacology. Therefore it is significant that a similar molecular design of PHTub-7 compared to its azobenzene analogues (PSTs) has ensured similar isomer-dependent bioactivity.…”

Section: Discussionmentioning

confidence: 99%

Pyrrole Hemithioindigo Antimitotics with Near-Quantitative Bidirectional Photoswitching Photocontrol Cellular Microtubule Dynamics with Single-Cell Precision

Sailer¹,

Meiring²,

Heise³

et al. 2021

Preprint

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<div> <div> <div> <p>Photoswitchably bioactive reagents, known as “photopharmaceuticals”, promise powerful applications in high-precision biological research. Yet most photoswitch scaffolds cannot be quantitatively bidirectionally photoisomerised, so they suffer from residual background activity that can confound experiments. We rationally designed photopharmaceuticals using the emerging near-quantitative photoswitch pyrrole hemithioindigo (<b>PHTubs</b>), to isomer-specifically inhibit the cytoskeletal protein tubulin. These <b>PHTub</b> reagents allow simultaneous visible-light imaging and photoswitching in live cells, where they could be used for cell-precise photomodulation of microtubule dynamics, and photocontrol over cell cycle progression and cell death. This is, as far as we know, the first use of a hemithioindigo photopharmaceutical for high-spatiotemporal-resolution biological control in live cells. This work opens up new horizons for high-precision microtubule research using <b>PHTubs</b>; and shows the cellular applicability of the near-quantitative photoswitch pyrrole hemithioindigo as a valuable scaffold for photocontrol of a range of other biological targets. </p> </div> </div> </div>

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“…15,21 We found that a complete reduction of the nitro group to the aniline 7 and oxidation with mCPBA is increasing the yield of the intramolecular cyclization from 39% to 62% (over two steps) for the unsubstituted diazocine 8c compared to the pathway via the hydroxylamine. 3-Bromo 8a and 3-iodo 8b compounds were obtained in 56% yield using the oxidative method of Trauner 22 with mCPBA. Fmoc groups were removed with NEt3 to yield NH-diazocines 9.…”

Section: Synthesismentioning

confidence: 99%

Substituted Nitrogen-Bridged Diazocines

Lentes¹,

Rudtke²,

Herges³

2021

Preprint

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Novel nitrogen bridged diazocines (triazocines) were synthesized that carry a formyl or an acetyl group at the CH2NR- bridge and bromo- or iodo substituents at the distant phenyl ring. The photophysical properties were investigated in acetonitrile and water. As compared to previous approaches the yields of the intramolecular azo cyclizations were increased (from ~40 to 60%) by an oxidative approach starting from the corresponding aniline precursors. The Z→E photoconversion yields in acetonitrile are 80-85% and the thermal half-lives of the metastable E configurations are 31-74 min. Particularly, the high photoconversion yields (~70%) of the water-soluble diazocines are noteworthy, which makes them promising candidates for applications in photopharmacology. The halogen substituents allow further functionalization via cross-coupling reactions.

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Oxidative Approach Enables Efficient Access to Cyclic Azobenzenes

Cited by 71 publications

References 65 publications

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Pyrrole Hemithioindigo Antimitotics with Near-Quantitative Bidirectional Photoswitching Photocontrol Cellular Microtubule Dynamics with Single-Cell Precision

Substituted Nitrogen-Bridged Diazocines

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