Isoquinoline-based biaryls as a robust scaffold for microtubule inhibitors

Kraus, Yvonne; Glas, Carina; Melzer, Benedikt; Gao, Li; Heise, Constanze; Preuße, Monique; Ahlfeld, Julia; Bracher, Franz; Thorn‐Seshold, Oliver

doi:10.1016/j.ejmech.2019.111865

Cited by 12 publications

(8 citation statements)

References 37 publications

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“…We aimed to formulate water-soluble SBTub prodrugs by phenol phosphorylationan approach that has been successful for other colchicinoid inhibitors (including clinically advanced CA4P, BNC105P, etc). 37 We had initially produced SBTub3P, the phosphate prodrug of previous lead compound SBTub3, however, its aqueous solubility was only moderate (<2 mg/mL) potentially due to aggregate formation by π-stacking of the planar compound. We synthesized SBTubA4P hoping that the out-of-plane central methoxy group would reduce π-stacking, which combined with the hydrophilicity of the three extra methoxy groups would give better solubility, as we have seen in other contexts.…”

Section: Resultsmentioning

confidence: 99%

“…Our second priority was to develop soluble SBTubs for in vivo use in multiorgan animal models, which do not easily tolerate even low amounts of organic cosolvents, and which may require temperatures below those of typical 2D cell cultures (e.g., <30 °C for zebrafish). We aimed to formulate water-soluble SBTub prodrugs by phenol phosphorylationan approach that has been successful for other colchicinoid inhibitors (including clinically advanced CA4P , BNC105P , etc) . We had initially produced SBTub3P , the phosphate prodrug of previous lead compound SBTub3 , however, its aqueous solubility was only moderate (<2 mg/mL) potentially due to aggregate formation by π-stacking of the planar compound.…”

Section: Resultsmentioning

confidence: 99%

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In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M

et al. 2022

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Photoswitchable reagents are powerful tools for high-precision studies in cell biology. When these reagents are globally administered yet locally photoactivated in two-dimensional (2D) cell cultures, they can exert micron-and millisecond-scale biological control. This gives them great potential for use in biologically more relevant three-dimensional (3D) models and in vivo, particularly for studying systems with inherent spatiotemporal complexity, such as the cytoskeleton. However, due to a combination of photoswitch isomerization under typical imaging conditions, metabolic liabilities, and insufficient water solubility at effective concentrations, the in vivo potential of photoswitchable reagents addressing cytosolic protein targets remains largely unrealized. Here, we optimized the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based on the styrylbenzothiazole (SBT) scaffold that are nonresponsive to typical fluorescent protein imaging wavelengths and so enable multichannel imaging studies. We applied these reagents both to 3D organoids and tissue explants and to classic model organisms (zebrafish, clawed frog) in one-and two-protein imaging experiments, in which spatiotemporally localized illuminations allowed them to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in vivo with cellular precision and second-level resolution. These nanomolar, in vivo capable photoswitchable reagents should open up new dimensions for high-precision cytoskeleton research in cargo transport, cell motility, cell division, and development. More broadly, their design can also inspire similarly capable optical reagents for a range of cytosolic protein targets, thus bringing in vivo photopharmacology one step closer to general realization.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M

et al. 2022

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“…In continuation of our recent work on the chemistry and pharmacology of benzylisoquinolines and related compounds [6][7][8][9][10][11][12][13][14] we investigated truncated analogues of the bisbenzylisoquino-line alkaloid tetrandrine as blockers of the calcium channel twopore channel 2 (TPC2), and identified 1-benzyl-1,2,3,4-tetrahydroisoquinolines bearing phenoxy and benzyloxy substituents (SG-005, SG-094; for structures of bioactive compounds mentioned in this text, see Figure S1 in Supporting Information File 1) on both aromatic rings as potent blockers with promising antitumor activity [15]. In this work we took advantage of the hitherto less explored N-acyl-Pictet-Spengler reaction and related chemistry based on the seminal work of Speckamp [16], where an N-acyl residue at the arylethylamine building block leads to enhanced cyclization rates due to the acid-mediated formation of highly electrophilic N-acyliminium intermediates [17].…”

Section: Introductionmentioning

confidence: 92%

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

Keller

Sauvageot-Witzku

Geisslinger

et al. 2021

Beilstein J. Org. Chem.

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We present a systematic investigation on an improved variant of the N-acyl-Pictet–Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N–H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure–activity relationships in this chemotype.

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“…Our second priority was to develop soluble SBTubs for in vivo use in multiorgan animal models, which do not easily tolerate even low amounts of organic cosolvents. We aimed to formulate water-soluble SBTub prodrugs by phenol phosphorylation -an approach that has been generally successful for colchicinoid inhibitors (including clinically-advanced CA4P, BNC105P etc) 34 . We had initially produced SBTub3P, the phosphate prodrug of previous lead compound SBTub3, however its aqueous solubility was only moderate (<2 mg/mL) potentially due to aggregate formation by π-stacking of the planar compound.…”

Section: Cellular Structure-activity Optimisation Of Sbtubsmentioning

confidence: 99%

In vivo photocontrol of microtubule dynamics and integrity, migration and mitosis, by the potent GFP-imaging-compatible photoswitchable reagents SBTubA4P and SBTub2M

Gao

Meiring

Varady

et al. 2021

Preprint

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Photoswitchable reagents to modulate microtubule stability and dynamics are an exciting tool approach towards micron- and millisecond-scale control over endogenous cytoskeleton-dependent processes. When these reagents are globally administered yet locally photoactivated in 2D cell culture, they can exert precise biological control that would have great potential for in vivo translation across a variety of research fields and for all eukaryotes. However, photopharmacology's reliance on the azobenzene photoswitch scaffold has been accompanied by a failure to translate this temporally- and cellularly-resolved control to 3D models or to in vivo applications in multi-organ animals, which we attribute substantially to the metabolic liabilities of azobenzenes. Here, we optimised the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based instead on the styrylbenzothiazole (SBT) photoswitch scaffold, that are non-responsive to the major fluorescent protein imaging channels and so enable multiplexed imaging studies. We applied these reagents to 3D systems (organoids, tissue explants) and classic model organisms (zebrafish, clawed frog) with one- and two-protein imaging experiments. We successfully used systemic treatment plus spatiotemporally-localised illuminations in vivo to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in these systems with cellular precision and second-level resolution. These nanomolar, in vivo-capable photoswitchable reagents can prove a game-changer for high-precision cytoskeleton research in cargo transport, cell motility, cell division and development. More broadly, their straightforward design can also inspire the development of similarly capable optical reagents for a range of protein targets, so bringing general in vivo photopharmacology one step closer to productive realisation.

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Isoquinoline-based biaryls as a robust scaffold for microtubule inhibitors

Cited by 12 publications

References 37 publications

In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M

In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

In vivo photocontrol of microtubule dynamics and integrity, migration and mitosis, by the potent GFP-imaging-compatible photoswitchable reagents SBTubA4P and SBTub2M

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