A fully synthetic 6-aza-artemisinin bearing an amphiphilic chain generates aggregates and exhibits anti-cancer activities

Koi, H.; Takahashi, Norihito; Fuchi, Yasufumi; Umeno, Tomohiro; Muramatsu, Yukiko; Seimiya, Hiroyuki; Karasawa, Satoru; Oguri, Hiroki

doi:10.1039/d0ob00919a

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…The few known “unnatural” amino peroxides reveal promising biological activity. For example, 11-aza-artemisinin, i.e., the product of replacement of the ester moiety of artemisinin with an amide group, is more potent against malaria than artemisinin itself. − Furthermore, both 11-aza-artemisinin and 6-aza-artemisinin exhibit anticancer activity. − …”

Section: Introductionmentioning

confidence: 99%

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

et al. 2021

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Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at −10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pK a units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C–O interaction with the two antiperiplanar C–O bonds. Due to the weakness of the complementary nO→σ*C–N donation from the peroxide oxygens (a consequence of “inverse α-effect”), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

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Section: Introductionmentioning

confidence: 99%

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

et al. 2021

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“…The introduction of a nitrogen atom next to a peroxide can significantly affect its activity toward the biological targets. For example, the higher efficiency of 11-aza-artemisinin and 6-aza-artemisinin against malaria and cancer in comparison to artemisinin demonstrate the potential of azaperoxides in medicinal chemistry. ,− …”

Section: Introductionmentioning

confidence: 99%

Inverse α-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities

et al. 2022

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Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of β,δ′-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the “stereoelectronic frustration” of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

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“…To construct supramolecular NPs in aqueous solutions, amphiphilic fragments with hydrophilic parts such as ions, biomaterials (DNA and peptides), and ethylene glycol chains are essential. However, supramolecular NPs tend to be polydisperse [7] …”

Section: Introductionmentioning

confidence: 99%

Push–Pull Bisnaphthyridylamine Supramolecular Nanoparticles: Polarity‐Induced Aggregation and Crystallization‐Induced Emission Enhancement and Fluorescence Resonance Energy Transfer

Hagihara

Umeno

Ueki

et al. 2020

Chemistry A European J

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Emissive push–pull‐type bisnaphthyridylamine derivatives (BNA‐X: X=Me, Et, Bzl, Ph, BuBr, and BuTEMPO) aggregate in aqueous methanol. Furthermore, a two‐step emission and aggregation process is controllable by varying the methanol‐to‐water ratio. At 2:3 MeOH/H2O, crystallization‐induced emission enhancement (CIEE) occurs via formation of an emissive crystal phase, whereas, at 1:9 MeOH/H2O, aggregation‐induced emission enhancement (AIEE) occurs, induced by emissive supramolecular nanoparticles (NPs). For BNA‐Ph, the emission quantum yield was 25 times higher in aqueous methanol than that in pure methanol. Despite the high hydrophobicity of BNA‐X (C log P=6.1–8.0), the spherical NPs were monodisperse (polydispersity indices <0.2). Moreover, the emissive NPs exhibited fluorescence resonance energy transfer (FRET) with pyrene; however, for BNA‐X bearing the TEMPO radical (BNA‐BuTEMPO), no FRET was observed because of quenching. In particular, the BNA‐BuTEMPO NPs have a slow rotational correlation time (1.3 ns), suggesting applications as magnetic resonance imaging contrast agents with large relaxivity.

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A fully synthetic 6-aza-artemisinin bearing an amphiphilic chain generates aggregates and exhibits anti-cancer activities

Abstract:
Appendage of an amphiphilic chain by exploiting the nitrogen installed on the 6-aza-artemisinin imparted self-assembling properties. The fully synthetic 6-aza-artemisinin formed aggregates and exhibited increased in vitro anti-cancer activities.

Cited by 12 publications

References 28 publications

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Inverse α-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities

Push–Pull Bisnaphthyridylamine Supramolecular Nanoparticles: Polarity‐Induced Aggregation and Crystallization‐Induced Emission Enhancement and Fluorescence Resonance Energy Transfer

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A fully synthetic 6-aza-artemisinin bearing an amphiphilic chain generates aggregates and exhibits anti-cancer activities

Abstract: Appendage of an amphiphilic chain by exploiting the nitrogen installed on the 6-aza-artemisinin imparted self-assembling properties. The fully synthetic 6-aza-artemisinin formed aggregates and exhibited increased in vitro anti-cancer activities.

Cited by 12 publications

References 28 publications

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Inverse α-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities

Push–Pull Bisnaphthyridylamine Supramolecular Nanoparticles: Polarity‐Induced Aggregation and Crystallization‐Induced Emission Enhancement and Fluorescence Resonance Energy Transfer

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Abstract:
Appendage of an amphiphilic chain by exploiting the nitrogen installed on the 6-aza-artemisinin imparted self-assembling properties. The fully synthetic 6-aza-artemisinin formed aggregates and exhibited increased in vitro anti-cancer activities.