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1.
Bioorg Med Chem ; 90: 117350, 2023 07 15.
Article in English | MEDLINE | ID: mdl-37270903

ABSTRACT

To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N-substituted N-arylsulfonamido d-valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)-d-valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1' substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2' substituent) were almost as active as the lead structure 1, making the latter derivative a suitable fluorescence imaging tool.


Subject(s)
Matrix Metalloproteinase 2 , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinase Inhibitors/pharmacology , Structure-Activity Relationship , Valine , Carboxylic Acids
2.
Bioorg Med Chem ; 28(22): 115726, 2020 11 15.
Article in English | MEDLINE | ID: mdl-33007549

ABSTRACT

Stereoisomeric 2-aryl-2-fluoro-cyclopropan-1-amines have been discovered as a new class of σ receptor ligands showing different selectivity for the two subtypes of the receptor. Generally, compounds substituted in 4-position are much more active than corresponding 3-substituted isomers. trans-2-Fluoro-2-(4-methoxyphenyl)cyclopropan-1-amine (19a) was the most potent (Ki = 4.8 nM) σ1 receptor ligand, while cis-2-fluoro-2-(4-trifluoromethylphenyl)cyclopropan-1-amine (20b) was the most potent (Ki = 95 nM) σ2 receptor ligand.


Subject(s)
Amines/pharmacology , Cyclopropanes/pharmacology , Receptors, sigma/metabolism , Amines/chemistry , Animals , Cyclopropanes/chemistry , Dose-Response Relationship, Drug , Guinea Pigs , Halogenation , Ligands , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship
3.
Bioconjug Chem ; 29(11): 3715-3725, 2018 11 21.
Article in English | MEDLINE | ID: mdl-30277751

ABSTRACT

Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivo monitoring of the activity of specific MMPs, therefore, provides high potential for assessing disease progression and tissue function, and manipulation of MMP activity in tissues and whole organisms may further provide a mode of controlling pathological processes. We describe here the synthesis of novel fluorinated and nonfluorinated analogues of a secondary sulfonamide-based lead structure, compound 2, and test their efficacy as in vivo inhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2 is a highly effective in vivo inhibitor of both MMP-2 and MMP-9 activity with little or no adverse effects even after long-term daily oral administration. A fluorescein-labeled derivative compound 17 shows direct binding to activated gelatinases surrounding inflammatory cuffs in the neuroinflammation model and to pancreatic ß-cells in the islets of Langerhans, colocalizing with MMP-2 and MMP-9 activity as detected using in situ zymography techniques. These results demonstrate that compound 2 derivatives have potential as in vivo imaging tools and for future development for specific MMP-2 versus MMP-9 probes. Our chemical modifications mainly target the residues directed toward the S1' and S2' pockets and, thereby, provide new information on the structure-activity relationships of this inhibitor type.


Subject(s)
Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cell Line , Female , Halogenation , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/enzymology , Insulin-Secreting Cells/metabolism , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 9/chemistry , Matrix Metalloproteinase Inhibitors/adverse effects , Matrix Metalloproteinase Inhibitors/chemical synthesis , Mice, Inbred C57BL , Molecular Docking Simulation , Structure-Activity Relationship , Sulfonamides/adverse effects , Sulfonamides/chemical synthesis
4.
Bioorg Med Chem Lett ; 27(10): 2099-2101, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28390942

ABSTRACT

We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.


Subject(s)
Enzyme Inhibitors/chemistry , Histone Demethylases/antagonists & inhibitors , Tranylcypromine/analogs & derivatives , B7-2 Antigen/metabolism , Biomarkers/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Halogenation , Histone Demethylases/metabolism , Histones/metabolism , Humans , Inhibitory Concentration 50 , Tranylcypromine/chemical synthesis , Tranylcypromine/toxicity
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