Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Corso, Alberto Dal; Borlandelli, Valentina; Corno, Cristina; Perego, Paola; Belvisi, Laura; Pignataro, Luca; Gennari, Cesare

doi:10.1002/ange.201916394

Cited by 13 publications

(22 citation statements)

References 55 publications

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“… 1514 It was therefore proposed that hydrolysis requires the prior protonation of the amine, and that the difference in the efficiency of hydrolysis between the tertiary amine and the aniline is due to their different basicities. 1514 Hydrolysis of the C4′–N bond is followed by intramolecular cyclization of the ethylenediamine linker, 1532 , 1533 resulting in the release of an alcohol as a leaving group. 1512 , 1524 , 1525 , 1534 Although the cyclization step is pH-dependent 1533 (proceeding more slowly at low pH), leaving group release efficiency was only reduced by a factor of 1.5 upon lowering the pH from 7.4 to 5.0.…”

Section: Photosensitized Release: From Small Molecules To Nanoparticlmentioning

confidence: 99%

“… 1514 Hydrolysis of the C4′–N bond is followed by intramolecular cyclization of the ethylenediamine linker, 1532 , 1533 resulting in the release of an alcohol as a leaving group. 1512 , 1524 , 1525 , 1534 Although the cyclization step is pH-dependent 1533 (proceeding more slowly at low pH), leaving group release efficiency was only reduced by a factor of 1.5 upon lowering the pH from 7.4 to 5.0. 1525 The overall chemical yield of uncaging (66–70%) correlated with the quantities of 405 and 406 formed during the reaction, suggesting that the light-independent steps are efficient.…”

Section: Photosensitized Release: From Small Molecules To Nanoparticlmentioning

confidence: 99%

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Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

et al. 2020

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Photoactivatable (alternatively, photoremovable, photoreleasable, or photocleavable) protecting groups (PPGs), also known as caged or photocaged compounds, are used to enable non-invasive spatiotemporal photochemical control over the release of species of interest. Recent years have seen the development of PPGs activatable by biologically and chemically benign visible and near-infrared (NIR) light. These long-wavelength-absorbing moieties expand the applicability of this powerful method and its accessibility to non-specialist users. This review comprehensively covers organic and transition metal-containing photoactivatable compounds (complexes) that absorb in the visible- and NIR-range to release various leaving groups and gasotransmitters (carbon monoxide, nitric oxide, and hydrogen sulfide). The text also covers visible- and NIR-light-induced photosensitized release using molecular sensitizers, quantum dots, and upconversion and second-harmonic nanoparticles, as well as release via photodynamic (photooxygenation by singlet oxygen) and photothermal effects. Release from photoactivatable polymers, micelles, vesicles, and photoswitches, along with the related emerging field of photopharmacology, is discussed at the end of the review.

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Section: Photosensitized Release: From Small Molecules To Nanoparticlmentioning

confidence: 99%

Section: Photosensitized Release: From Small Molecules To Nanoparticlmentioning

confidence: 99%

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

et al. 2020

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“…nitro, amide, azide). Upon application of the specific stimulus, the covalent bond between the trigger and the self-immolative linker undergoes a cascade of disassembly reactions ultimately leading to release of the active molecule [35,36]. From a mechanistic point of view, after the stimulus activates the trigger group, drug or payload release is thermodynamically driven and takes place via either an electron cascade for PABC-type linkers (1,4-, 1,6-, or 1,8-elimination) or an intramolecular nucleophilic cyclisation (Fig.…”

Section: Self-immolative Linkersmentioning

confidence: 99%

Self-immolative Linkers in Prodrugs and Antibody Drug Conjugates in Cancer Treatment

Ramarao

Tyndall

Gamble

2021

PRA

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Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. Key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety. Objective: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells. Methods: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years to 2020. Results: The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione), by over-expressed enzymes (cathepsin, plasmin, β-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site. Conclusion: This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promising results in therapeutic applications.

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“…Carbamates and allylic carbamates in particular, are of considerable interest due to their important role in various areas. Indeed, they belong to structural or functional part of many approved drugs [1][2][3][4][5] and prodrugs [6], which are used for the treatment of various diseases such as Alzheimer's disease [7], cancer [8], hepatitis C [1,9], HIV infection [10], anxiety [11] and epilepsy [11]. They are found to be important raw materials in the synthesis of polyurethanes [12][13][14], paints [15], wood preservatives [15], pesticides, herbicides, insecticides and fungicides [16].…”

Section: Introductionmentioning

confidence: 99%