Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Cadahía, Jorge Peiró; Bondebjerg, Jon; Hansen, Christian A.; Previtali, Viola; Hansen, Anders Elias; Andresen, Thomas Lars; Clausen, Mads Hartvig

doi:10.1021/acs.jmedchem.7b01775

Cited by 57 publications

(54 citation statements)

References 69 publications

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“…Similar to this approach, the phenylboronic acid prodrug 49 ( Figure 6 ) of methotrexate ( 48 , Figure 6 ) was designed for a more selective and effective treatment of rheumatoid arthritis (RA), since the presence of high levels of ROS in inflammatory cells is associated with RA pathology [ 52 ].…”

Section: Synthesis and Biological Applications Of Boronic Acids Dementioning

confidence: 99%

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

et al. 2020

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Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly.

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Section: Synthesis and Biological Applications Of Boronic Acids Dementioning

confidence: 99%

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

et al. 2020

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“…These functional groups undergo self-immolation under some specific triggering conditions (trifluoroacetic acid, piperidine), which in turn releases the attached cargo [ 177 , 178 ]. Redox-triggered self-immolative linkers could be broadly divided into three categories by triggers: transition metal (e.g., Zn, Pd) based reagents [ 179 , 180 , 181 ], reducing reagents (DTT, GSH or TCEP) [ 182 ], and oxidant (e.g., H 2 O 2 ) [ 183 , 184 , 185 , 186 ]. Disulfide bonds are the most widely used reductant-responsive linkers.…”

Section: Stimulus-responsive Systemsmentioning

confidence: 99%

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

Liu

Lovell

Zhang

et al. 2020

IJMS

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Stimulus-responsive drug delivery systems generally aim to release the active pharmaceutical ingredient (API) in response to specific conditions and have recently been explored for disease treatments. These approaches can also be extended to molecular imaging to report on disease diagnosis and management. The stimuli used for activation are based on differences between the environment of the diseased or targeted sites, and normal tissues. Endogenous stimuli include pH, redox reactions, enzymatic activity, temperature and others. Exogenous site-specific stimuli include the use of magnetic fields, light, ultrasound and others. These endogenous or exogenous stimuli lead to structural changes or cleavage of the cargo carrier, leading to release of the API. A wide variety of stimulus-responsive systems have been developed—responsive to both a single stimulus or multiple stimuli—and represent a theranostic tool for disease treatment. In this review, stimuli commonly used in the development of theranostic nanoplatforms are enumerated. An emphasis on chemical structure and property relationships is provided, aiming to focus on insights for the design of stimulus-responsive delivery systems. Several examples of theranostic applications of these stimulus-responsive nanomedicines are discussed.

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“…Deprotection of the boc-moiety was performed using a mixture of trifluoroacetic acid (TFA) in dichloromethane to yield the corresponding TFA salt of prodrug A. However, standard procedures described in the literature to couple compound 2 via transformation into a chloroformate did not yield the desired product 3 [23]. In the case of the alkylated prodrug B, alcohol 2 was oxidized to the corresponding aldehyde 4 using 2-iodobenzoic acid (IBX) in DMSO (Scheme 2A).…”

Section: Synthesismentioning

confidence: 99%

“…One characteristic difference of cancer cells is an up to ten-fold higher concentration of reactive oxygen species (ROS) like hydrogen peroxide (H 2 O 2 ) [20] compared to healthy tissues [21]. As a trigger moiety for ROS-mediated prodrug activation, boronic acids have been used, for example, for anticancer drugs like aminoferrocene [22], antifolates [23] or several alkylating agents [24]. In the case of phenylboronic acid trigger units, upon reaction with H 2 O 2 , the generated boric acid is readily hydrolyzed, and the free drug is released via an electron-migration cascade with simultaneous formation of a quinone methide species from the linker moiety (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib

et al. 2020

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Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients’ quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with H2O2 and their stability in cell culture medium and serum. Finally, the biological activity of the prodrugs was investigated in three cancer cell lines and revealed a good correlation between activity and intrinsic H2O2 levels of the cells for prodrug A. Furthermore, the activity of this prodrug was distinctly reduced in a non-malignant, c-MET expressing human lung fibroblast (HLF) cell line.

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Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Cited by 57 publications

References 69 publications

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib

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