Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.
Copyright © 2020 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Actinobacteria / metabolism
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzamides / antagonists & inhibitors*
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Cell Line, Tumor
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Cell Movement / drug effects
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Cyclohexanones / antagonists & inhibitors*
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Cyclohexanones / chemical synthesis
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Glyoxylates / antagonists & inhibitors
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Glyoxylates / metabolism
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Humans
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Matrix Metalloproteinase 11 / drug effects
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Matrix Metalloproteinase 11 / metabolism
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Matrix Metalloproteinase 2 / drug effects
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / drug effects
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinases / drug effects*
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Matrix Metalloproteinases / metabolism*
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Models, Molecular
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NF-kappa B / drug effects*
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit / metabolism
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Neoplasm Invasiveness
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Neoplasms
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Quinones / chemistry
Substances
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Antineoplastic Agents
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Benzamides
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Cyclohexanones
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Glyoxylates
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NF-kappa B
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NF-kappa B p50 Subunit
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NFKB1 protein, human
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Quinones
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dehydroxymethylepoxyquinomicin
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epoxyquinomicin C
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ketomycin
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Matrix Metalloproteinase 11
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Matrix Metalloproteinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9