New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

Behrends, Malte; Wagner, Stefan; Kopka, Klaus; Schober, Otmar; Schäfers, Michael; Kumbhar, Sadhana; Waller, Mark P.; Haufe, Günter

doi:10.1016/j.bmc.2015.03.078

Cited by 19 publications

(16 citation statements)

References 57 publications

(55 reference statements)

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“…Marimastat (MATT) is a potent MMP inhibitor and acts by mimicking the substrate of the MMPs to work with MMPs in a competitive and reversible pattern 6 , 7 . MATT enables the downregulation of MMPs, especially MMP-1, MMP-2, MMP-7, MMP-9 and MMP-14, by 50%, even at nanomolar concentrations less than 5 nM.…”

Section: Introductionmentioning

confidence: 99%

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Zhao

Zhu

et al. 2018

Theranostics

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Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/β-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs.Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by förster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse.Results: The interaction between the prodrug and complexes is strong with a high affinity, resulting in the assembly of these two components into hybrid nanoparticles (250 nm). Compared with extracellular incubation with MATT, HPMC NP treatment markedly reduced the expression (100%) and activity (50%) of MMPs in 4T1 cells and in the tumor. HPMC NPs exhibited 1.4-fold tumor accumulation, inhibited tumor-growth by >8-fold in volume with efficient apoptosis and proliferation, and suppressed metastasis (>5-fold) and angiogenesis (>3-fold). Overall, HPMC NPs were efficient in metastatic cancer therapy. Conclusions: According to the assembly of polymer prodrug and protein-drug complexes, this study offers a new strategy for constructing nanoparticles for targeted drug delivery, biomedical imaging, and combinatorial treatment. Importantly, via inhibition of intracellular MMPs, metastasis and angiogenesis can be potently blocked, benefiting the rational design of nanomedicine for cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Zhao

Zhu

et al. 2018

Theranostics

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“…[3] Severale nzymes producing or metabolizing d-amino acids have been discovered. [4] d-2-Aminobutyric acid, which is an unnatural amino acid, has been widely used in the synthesis of antibiotics, [5] angiotensin-converting enzyme 2i nhibitors, [6] brain-permeable polo-like kinase-2( Plk-2) inhibitors, [7] matrix metalloproteinase inhibitors, [8] and antiproliferatives. [9] Generally speaking, resolution of the racemate of aamino acids is currently the main method to obtaint he optically pure d-amino acids.…”

Section: Introductionmentioning

confidence: 99%

Highly Atom Economic Synthesis of d‐2‐Aminobutyric Acid through an In Vitro Tri‐enzymatic Catalytic System

et al. 2017

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d‐2‐Aminobutyric acid is an unnatural amino acid serving as an important intermediate in pharmaceutical production. Developing a synthetic method that uses cheaper starting materials and produces less by‐product is a pressing demand. A tri‐enzymatic catalytic system, which is composed of l‐threonine ammonia lyase (l‐TAL), d‐amino acid dehydrogenase (d‐AADH), and formate dehydrogenase (FDH), has thus been developed for the synthesis of d‐2‐aminobutyric acid with high optical purity. In this cascade reaction, the readily available l‐threonine serves as the starting material, carbon dioxide and water are the by‐products. d‐2‐Aminobutyric acid was obtained with >90 % yield and >99 % enantioselective excess, even without adding external ammonia, demonstrating that the ammonia from the first reaction can serve as the amino donor for the reductive amination step. This multi‐enzymatic system provides an attractive method with high atomic economy for the synthesis of d‐α‐amino acids from the corresponding l‐α‐amino acids, which are readily produced by fermentation.

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“…In a patent from University of Münster and Siemens Medical Solutions, two fluorine-18-labeled matrix metalloproteinase inhibitors are described [185]. Their work was recently published in the literature but did not include a description of their fluorine-18-labeled compounds HUG 74 (86) and HUG 78 (87) ( Figure 45) [186]. The interest in matrix metalloproteinase stems from its upregulation in pathologies like atherosclerosis, tumorigenesis and other inflammatory diseases (authors claim usefulness in detecting the following diseases where matrix metalloproteinases are upregulated: atherosclerosis, congestive heart failure, cancer, arthritis, amyotrophic lateral sclerosis, brain metastases, cerebrovascular diseases, Alzheimer's disease, chronic obstructive pulmonary disease).…”

Section: Matrix Metalloproteinasementioning

confidence: 99%

Fluorine-18 Patents (2009–2015). Part 1: Novel Radiotracers

et al. 2015

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New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

Cited by 19 publications

References 57 publications

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Highly Atom Economic Synthesis of d‐2‐Aminobutyric Acid through an In Vitro Tri‐enzymatic Catalytic System

Fluorine-18 Patents (2009–2015). Part 1: Novel Radiotracers

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