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Bioorganic & Medicinal Chemistry Letters Jul 2022Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the...
Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC = 0.721 µM) compared to MAO-B (IC = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.
Topics: Humans; Indans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Parkinson Disease; Propylamines; Selegiline; Tetrahydronaphthalenes; Tyramine
PubMed: 35447344
DOI: 10.1016/j.bmcl.2022.128746 -
The Journal of Organic Chemistry May 2022An efficient copper-catalyzed cascade annulation of -hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a...
An efficient copper-catalyzed cascade annulation of -hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a series of valuable pyrano[2,3-]pyrazoles with good yields across a wide range of substrates in a simple fashion. This novel reaction involves the formation of alkynyl -quinone methides, a 1,4-conjugate addition, and a subsequent 6-endo cyclization process. The mechanistic elucidation is well supported by control experiment and literature precedents.
Topics: Catalysis; Copper; Pargyline; Propylamines; Pyrazoles; Pyrazolones
PubMed: 35442039
DOI: 10.1021/acs.joc.2c00122 -
Organic & Biomolecular Chemistry May 2022A highly regio- and chemoselective synthesis of 1-isoindoliums through a facile and novel cascade cyclization reaction of propargylamine-based 1,6-diynes under mild...
A highly regio- and chemoselective synthesis of 1-isoindoliums through a facile and novel cascade cyclization reaction of propargylamine-based 1,6-diynes under mild conditions has been developed. Different functional groups were compatible under the optimized reaction conditions, giving the corresponding products in up to 94% yields. Upon treatment with a base, the alkyne moiety of 1-isoindoliums could be further transformed to allenes in excellent yields.
Topics: Catalysis; Cyclization; Diynes; Halogenation; Molecular Structure; Pargyline; Propylamines
PubMed: 35420116
DOI: 10.1039/d2ob00316c -
The Journal of Organic Chemistry May 2022An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room...
An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room temperature and results in 3-aryl-5-arylethynyl-1-phenyl-4,5-dihydro-1-pyrazoles with up to 57-73% yields. Under similar conditions, the cyclocondensation of conjugated 2,4,1-enynones with arylhydrazine proceeds only in the presence of cyclic amines. 1,5-Diaryl-3-X-pent-4-yn-1-ones are reported as synthetic equivalents of conjugated 2,4,1-enynones in reactions with arylhydrazines. On the basis of obtained data, there are highly efficient methods developed for the synthesis of 5-arylethynyl-substituted 4,5-dihydro-1-pyrazoles, as well as for similarly structured 1-pyrazoles prepared by oxidation in AcOH. Presented products possess quite marked fluorescent abilities. Emission maximum wavelengths are located at 453-465 and 363-400 nm, respectively; certain compounds show extremely large Stokes shifts that may reach 91,000 cm.
Topics: Acetylene; Alkynes; Ketones; Pargyline; Propylamines; Pyrazoles
PubMed: 35394780
DOI: 10.1021/acs.joc.2c00198 -
Bioorganic Chemistry May 2022A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and...
A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer's disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC = 99.0 nM; HDAC1, IC = 21.4 nM) and excellent MAO selectively (MAO-A, IC = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aβ1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Drug Design; Hydroxamic Acids; Mice; Mice, Inbred ICR; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Propylamines; Structure-Activity Relationship
PubMed: 35305483
DOI: 10.1016/j.bioorg.2022.105724 -
Journal of Experimental & Clinical... Feb 2022Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment...
BACKGROUND
Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1 and PYCR2) are two mitochondrial enzymes that facilitate the last step in the glutamine-to-proline conversion. Overexpression of PYCR1 is involved in progression of several cancers, however, its' role in hematological cancers is unknown. In this study, we investigated whether PYCR affects MM viability, proliferation and response to bortezomib.
METHODS
Correlation of PYCR1/2 with overall survival was investigated in the MMRF CoMMpass trial (653 patients). OPM-2 and RPMI-8226 MM cell lines were used to perform in vitro experiments. RPMI-8226 cells were supplemented with C-glutamine for 48 h in both normoxia and hypoxia (< 1% O, by chamber) to perform a tracer study. PYCR1 was inhibited by siRNA or the small molecule inhibitor pargyline. Apoptosis was measured using Annexin V and 7-AAD staining, viability by CellTiterGlo assay and proliferation by BrdU incorporation. Differential protein expression was evaluated using Western Blot. The SUnSET method was used to measure protein synthesis. All in vitro experiments were performed in hypoxic conditions.
RESULTS
We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis. Finally, combination therapy of pargyline with bortezomib reduced viability in CD138 MM cells and reduced tumor burden in the murine 5TGM1 model compared to single agents.
CONCLUSIONS
This study identifies PYCR1 as a novel target in bortezomib-based combination therapies for MM.
Topics: Animals; Antineoplastic Agents; Bortezomib; Cell Proliferation; Humans; Mice; Multiple Myeloma; Protein Synthesis Inhibitors; Pyrroline Carboxylate Reductases; Survival Analysis
PubMed: 35105345
DOI: 10.1186/s13046-022-02250-3 -
World Journal of Diabetes Jan 2022When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
BACKGROUND
When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
AIM
To test whether catecholamines activate glucose transport in human adipocytes.
METHODS
The uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine).
RESULTS
In human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.
CONCLUSION
High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.
PubMed: 35070058
DOI: 10.4239/wjd.v13.i1.37 -
Journal of Medicinal Chemistry Feb 2022Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development,...
Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated -methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC from 0.03 to <0.0001 μM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.
Topics: Acetylation; Animals; Cell Line, Tumor; Cell Proliferation; Drug Design; Enzyme Inhibitors; Glioma; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Isoenzymes; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Pargyline; Propylamines; Structure-Activity Relationship; Transplantation, Heterologous
PubMed: 35005974
DOI: 10.1021/acs.jmedchem.1c01726 -
ACS Pharmacology & Translational Science Dec 2021Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the...
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
PubMed: 34927013
DOI: 10.1021/acsptsci.1c00223 -
Journal of Medicinal Chemistry Dec 2021Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent...
Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate cancer agents. Resultantly, compound elicited magnificent cell growth inhibitory effects against the PC-3 and DU-145 cell lines and led to remarkable suppression of tumor growth in human prostate PC-3 and DU-145 xenograft nude mouse models. The outcome of the enzymatic assays ascertained that the substantial antiproliferative effects of compound were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid demonstrates good human hepatocytic stability and good oral bioavailability in rats and exhibits enough promise to emerge as a therapeutic for the treatment of prostate cancer in the near future.
Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Histone Demethylases; Humans; Male; Pargyline; Prostatic Neoplasms
PubMed: 34908406
DOI: 10.1021/acs.jmedchem.1c00966