Glycosidase activated prodrugs for targeted cancer therapy

Martin, Harlei; Lázaro, Laura Ramírez; Gunnlaugsson, Thorfinnur; Scanlan, Eoin M.

doi:10.1039/d2cs00379a

Cited by 46 publications

(37 citation statements)

References 108 publications

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“…Since probes targeting different CPs with different colors can be prepared with our design strategy, we believe that multicolor imaging of plural CPs’ activities can be performed. We also believe the activation mechanism of “CP-triggered fluorophore release” used in this study can be extended in principle to develop functional molecules that can release drugs or photosensitizers upon reaction with CPs. Thus, our modular design strategy for CPs-targeted fluorescence probes should be useful for developing functional molecules as well as for studying CP-related biological and pathological phenomena.…”

Section: Discussionmentioning

confidence: 96%

Modular Design Platform for Activatable Fluorescence Probes Targeting Carboxypeptidases Based on ProTide Chemistry

Kuriki,

Sogawa,

Komatsu

et al. 2023

J. Am. Chem. Soc.

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Carboxypeptidases (CPs) are a family of hydrolases that cleave one or more amino acids from the C-terminal of peptides or proteins and play indispensable roles in various physiological and pathological processes. However, only a few highly activatable fluorescence probes for CPs have been reported, and there is a need for a flexibly tunable molecular design platform to afford a range of fluorescence probes for CPs for biological and medical research. Here, we focused on the unique activation mechanism of ProTide-based prodrugs and established a modular design platform for CP-targeting florescence probes based on ProTide chemistry. In this design, probe properties such as fluorescence emission wavelength, reactivity/ stability, and target CP can be readily tuned and optimized by changing the four probe modules: the fluorophore, the substituent on the phosphorus atom, the linker amino acid at the P1 position, and the substrate amino acid at the P1′ position. In particular, switching the linker amino acid at position P1 enabled us to precisely optimize the reactivity for target CPs. As a proof-of-concept, we constructed probes for carboxypeptidase M (CPM) and prostate-specific membrane antigen (also known as glutamate carboxypeptidase II). The developed probes were applicable for the imaging of CP activities in live cells and in clinical specimens from patients. This design strategy should be useful in studying CP-related biological and pathological phenomena.

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Section: Discussionmentioning

confidence: 96%

Modular Design Platform for Activatable Fluorescence Probes Targeting Carboxypeptidases Based on ProTide Chemistry

Kuriki,

Sogawa,

Komatsu

et al. 2023

J. Am. Chem. Soc.

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“…Vaidya and Patra presented an overview of glycoconjugation as an attractive strategy to impart selectivity and improve pharmacokinetics of platinum-based anticancer agents [ 78 ]. An interesting critical review article on the topic of progress (over the past decade 2010–2020) in glycoconjugation of anticancer drugs describes Fu et al [ 79 ] and the Martin group [ 80 ]. The review works testify to the multitude of works carried out on improving the properties of platinum-based drugs using the glycoconjugation strategy and, consequently, the great interest in this subject.…”

Section: Glycoconjugatesmentioning

confidence: 99%

A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy

et al. 2023

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The number of cancer-related diseases is still growing. Despite the availability of a large number of anticancer drugs, the ideal drug is still being sought that would be effective, selective, and overcome the effect of multidrug resistance. Therefore, researchers are still looking for ways to improve the properties of already-used chemotherapeutics. One of the possibilities is the development of targeted therapies. The use of prodrugs that release the bioactive substance only under the influence of factors characteristic of the tumor microenvironment makes it possible to deliver the drug precisely to the cancer cells. Obtaining such compounds is possible by coupling a therapeutic agent with a ligand targeting receptors, to which the attached ligand shows affinity and is overexpressed in cancer cells. Another way is to encapsulate the drug in a carrier that is stable in physiological conditions and sensitive to conditions of the tumor microenvironment. Such a carrier can be directed by attaching to it a ligand recognized by receptors typical of tumor cells. Sugars seem to be ideal ligands for obtaining prodrugs targeted at receptors overexpressed in cancer cells. They can also be ligands modifying polymers’ drug carriers. Furthermore, polysaccharides can act as selective nanocarriers for numerous chemotherapeutics. The proof of this thesis is the huge number of papers devoted to their use for modification or targeted transport of anticancer compounds. In this work, selected examples of broad-defined sugars application for improving the properties of both already-used drugs and substances exhibiting anticancer activity are presented.

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“…For the treatment of cancer, glycosidic prodrugs based on the organic antibiotic duocarmycin sa were created using prodrug monotherapy and antibodydirected enzyme prodrug therapy (Figure 12). [75,76]…”

Section: Glycosidic Linkage In Prodrug Designmentioning

confidence: 99%

Prodrug Rewards in Medicinal Chemistry: An Advance and Challenges Approach for Drug Designing

Husain,

Monga,

Narwal

et al. 2023

Chemistry & Biodiversity

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This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications. Prodrugs are chemicals that are supplied inactively, but then go through enzymatic and chemical transformation in vivo to release the active parent medication that can have the desired pharmacological effect. By adding an inactive chemical moiety, prodrugs are improved in a number of ways that contribute to their potency and durability. For the purpose of illustrating the usefulness of the prodrug approach, this review covers examples of prodrugs that have been made available or are now undergoing human trials. Additionally, it included lists of the most common functional groups, carrier linkers, and reactive chemicals that can be used to create prodrugs. The current study also provides a brief introduction, several chemical methods and modifications for creating prodrugs and mutual prodrugs, as well as an explanation of recent advancements and difficulties in the field of prodrug design. The primary chemical carriers employed in the creation of prodrugs, such as esters, amides, imides, NH‐acidic carriers, amines, alcohols, carbonyl, carboxylic, and azo‐linkages, are also discussed. This review also discusses glycosidic and triglyceride mutually activated prodrugs, which aim to deliver the drugs after bioconversion at the intended site of action. The article also discusses the extensive chemistry and wide variety of applications of recently approved prodrugs, such as antibacterial, anti‐inflammatory, cardiovascular, antiplatelet, antihypertensive, atherosclerotic, antiviral, etc. In order to illustrate the prodrug and mutual drug concept's various applications and highlight its many triumphs in overcoming the formulation and delivery of problematic pharmaceuticals, this work represents a thorough guide that includes the synthetic moiety for the reader.

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Glycosidase activated prodrugs for targeted cancer therapy

Abstract: In this review glycosidase activated prodrugs that target cancer cells are discussed.

Cited by 46 publications

References 108 publications

Modular Design Platform for Activatable Fluorescence Probes Targeting Carboxypeptidases Based on ProTide Chemistry

Modular Design Platform for Activatable Fluorescence Probes Targeting Carboxypeptidases Based on ProTide Chemistry

A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy

Prodrug Rewards in Medicinal Chemistry: An Advance and Challenges Approach for Drug Designing

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