Triazolyl Derivatives for Acidic Release of Alcohols

Mondon, Martine; Delatouche, Régis; Bachmann, Christian; Frapper, Gilles; Len, Christophe; Bertrand, Philìppe

doi:10.1002/ejoc.201001677

Cited by 10 publications

(5 citation statements)

References 37 publications

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“…Our linker system is comprised of a diamine-derived cyclisation spacer 14 connected in series to a triazole 1,4-elimination spacer ( Scheme 1 ). 16 Incorporating a diamine-derived spacer next to the triazole ring permits the use of carbamate trigger groups, 17 which drastically expands the scope of ester triggers reported previously. 18 Removal of the trigger group from 1 under basic conditions exposes a secondary amine nucleophile ( 2 ) that undergoes a cyclisation–elimination reaction to afford a cyclic urea ( 3 ) and a short-lived triazolyl-1-methanol species.…”

Section: Resultsmentioning

confidence: 99%

Dynamic pH responsivity of triazole-based self-immolative linkers

et al. 2020

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Gating the release of chemical payloads in response to transient signals is an important feature of 'smart' delivery systems. Herein, we report a triazole-based self-immolative linker that can be reversibly paused or slowed and restarted throughout its elimination cascade in response to pH changes in both organic and organic-aqueous solvents. The linker is conveniently prepared using the alkyne-azide cycloaddition reaction, which introduces a 1,4-triazole ring that expresses a pH-sensitive intermediate during its elimination sequence. Using a series of model compounds, we demonstrate that this intermediate can be switched between active and dormant states depending on the presence of acid or base, cleanly gating the release of payload in response to a fluctuating external stimulus.

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Section: Resultsmentioning

confidence: 99%

Dynamic pH responsivity of triazole-based self-immolative linkers

et al. 2020

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“…These results also indicated that the hydroxamic acid pro-drugs are more stable than the benzamide ones for the same R group. Pro-drugs of alcohols like uridine were also previously evaluated and are even more stable, where the best system is the dimethoxyphenyl 5c for a convenient half-life of 6-7 h at pH 5 [26].…”

Section: Discussionmentioning

confidence: 99%

“…The synthesis of pro-drugs (Scheme 1), the determination of the hydrolysis rates of pro-drugs in mildly acidic pH [25,26], the pro-drug-functionalized macromonomer-PEO-CI994 (17), the pro-drug-functionalized macro-monomer-PEO-SAHA (16), the pro-drug-functionalized macro-monomer-PEO-NODH (15), and the synthesis of the pro-drug functionalized nanoparticles (NPs) (Figure 1), and the biological tests are developed in the supporting information part.…”

Section: Discussionmentioning

confidence: 99%

The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

2019

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Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

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“…3 Covalent acid-sensitive linkers are used to connect drugs to vectors 4 to exploit the acidic process of endocytosis. We recently described amine 5 and alcohol 6 release (Scheme 1, X = NH or O respectively) based on an acid-sensitive triazolyl system obtained by click chemistry 7 and report herein new findings for the release of aniline.…”

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confidence: 97%

Extending Triazolyl-Based Release under Mildly Acidic Conditions To Give Aniline Derivatives

Delatouche¹,

Bachmann²,

Frapper³

et al. 2012

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Triazolyl derivatives of anilines were prepared and evaluated as releasing systems at mildly acidic pH values. Two triazolyl derivatives showed convenient pH sensitivity, being stable at pH 7.3 and rapidly hydrolyzed at pH values below 5. A generalized mechanism is proposed from additional theoretical investigations.Drug delivery systems (DDS) are developed to exploit endocytosis 1 and enhance permeability and retention effects, 2 with progressive or differentiated release being extensively investigated. 3 Covalent acid-sensitive linkers are used to connect drugs to vectors 4 to exploit the acidic process of endocytosis. We recently described amine 5 and alcohol 6 release (Scheme 1, X = NH or O respectively) based on an acid-sensitive triazolyl system obtained by click chemistry 7 and report herein new findings for the release of aniline. Scheme 1 Principle of triazolyl-based acid-sensitive systemsTwo synthetic pathways were investigated to prepare aniline carbamates A (Scheme 1, Y = CO 2 , R 4 = Ph) and alkylanilines B (Scheme 1, Y = no atom, R 4 = Ph). In path A (Scheme 2), propargylic carbamates 2 were prepared from alcohols 1. The reaction with alcohols 1a and 1c proceeded in good yields, however, although alcohols 1b and 1d were consumed, the corresponding carbamates 2b and 2d were probably unstable and could not be isolated. 8 Cycloaddition of 2a with azide 3 gave carbamate 4a in modest yield. The cycloaddition of 2c resulted in decomposition. In path B, the known alcohols 5a-d were prepared in high yields and reacted with phenyl isocyanate to give carbamates 4. Carbamate 4a was isolated in higher yield than that obtained using path A. The syntheses of carbamates 4b-d remained problematic. Alcohol 5b gave carbamate 4b together with the inseparable alkene 8b. For alcohols 5c and 5d, two rearranged amine derivatives 6c and 6d were isolated in very high yields instead of the expected carbamates 4c and 4d. The structures of alkylamines 6c and 6d were confirmed by their preparation from alcohols 5 (path B), via chlorides 7 and substitution with aniline (Scheme 2, iii-v). Since dianisyl chlorides can easily be converted into alcohols, 9 this may explain the low yields observed with the chlorination method. Amines 6c and 6d were obtained in moderate yields compared to the in situ rearrangement of carbamates 4c and 4d. Derivatives 6a and 6b were not prepared because they were expected to be stable at low pH. The syntheses of amines 6c and 6d appeared to be more effective via the rearrangement of carbamates 4c and 4d, which are probably formed in situ.The carbamate 4a and alkylamines 6c and 6d were submitted to acidic hydrolysis (citrate buffer for pH 4.3 and TRIZMA buffer for physiological pH). Half-lives (t 1/2 ) are A , Y = CO 2 B , Y = no atom a R 1 = R 2 = Me b R 1 = Me, R 2 = Ph c R 1 = R 2 = Ph d R 1 = R 2 = p-MeOC 6 H 4

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Triazolyl Derivatives for Acidic Release of Alcohols

Cited by 10 publications

References 37 publications

Dynamic pH responsivity of triazole-based self-immolative linkers

Dynamic pH responsivity of triazole-based self-immolative linkers

The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Extending Triazolyl-Based Release under Mildly Acidic Conditions To Give Aniline Derivatives

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