Publications by authors named "Elina M Jarho"

17 Publications

  • Page 1 of 1

A scaffold replacement approach towards new sirtuin 2 inhibitors.

Bioorg Med Chem 2020 01 30;28(2):115231. Epub 2019 Nov 30.

Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.
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http://dx.doi.org/10.1016/j.bmc.2019.115231DOI Listing
January 2020

Identification of the Binding Site of Chroman-4-one-Based Sirtuin 2-Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry.

J Med Chem 2016 12 21;59(23):10794-10799. Epub 2016 Nov 21.

Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , Kemivagen 10, SE-41296 Göteborg, Sweden.

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01117DOI Listing
December 2016

BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses.

Chembiochem 2015 Sep 13;16(14):1997-2001. Epub 2015 Aug 13.

School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.

Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl- ases such as sirtuin 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro-inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age-related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins.
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http://dx.doi.org/10.1002/cbic.201500272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600234PMC
September 2015

Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells.

J Med Chem 2014 Dec 2;57(23):9870-88. Epub 2014 Dec 2.

Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , Kemivagen 10, SE-412 96 Göteborg, Sweden.

Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
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http://dx.doi.org/10.1021/jm500930hDOI Listing
December 2014

AROS has a context-dependent effect on SIRT1.

FEBS Lett 2014 May 26;588(9):1523-8. Epub 2014 Mar 26.

School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

The modulation of protein deacetylase SIRT1 has a vast therapeutic potential in treatment of several aging-associated diseases. Active regulator of SIRT1 (AROS) is a small endogenous protein which was originally reported to activate SIRT1 through a direct interaction in cancer cells. We show that the interaction between the two proteins is weak and does not alter the activity of SIRT1 in non-cancerous human cells. The results of different in vitro SIRT1 activity assays disclosed AROS as an inhibitor of SIRT1. The functional relationship between AROS and SIRT1 proved to be dependent on the biological context and experimental setting.
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http://dx.doi.org/10.1016/j.febslet.2014.03.020DOI Listing
May 2014

Screen of pseudopeptidic inhibitors of human sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells.

J Med Chem 2013 Sep 22;56(17):6681-95. Epub 2013 Aug 22.

School of Pharmacy and ∥Department of Neurology, Institute of Clinical Medicine , University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase.
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http://dx.doi.org/10.1021/jm400438kDOI Listing
September 2013

Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors.

J Med Chem 2012 Aug 7;55(16):7104-13. Epub 2012 Aug 7.

Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
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http://dx.doi.org/10.1021/jm3005288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426190PMC
August 2012

N(epsilon)-thioacetyl-lysine-containing tri-, tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors.

J Med Chem 2009 Apr;52(7):2153-6

Department of Pharmaceutical Chemistry, Institute of Clinical Medicine, University of Kuopio, Kuopio, Finland.

N()-Thioacetyl-lysine-containing tri-, tetra-, and pentapeptides, based on the alpha-tubulin and p53 protein sequences, were studied as SIRT1 and SIRT2 inhibitors. The potency of the pentapeptides depended on the selection of the side chains. The removal of N- and C-terminal residues of the pentapeptides yielded tripeptides with retained SIRT1 inhibitory activity but decreased SIRT2 inhibitory activity. The most potent SIRT1 inhibitors were equipotent with the reference compound (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) with the IC(50) values of 180-330 nM.
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http://dx.doi.org/10.1021/jm801401kDOI Listing
April 2009

Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats.

Basic Clin Pharmacol Toxicol 2007 Feb;100(2):132-8

Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland.

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-month-old) and old (8- to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP(3)) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP(3) concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.
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http://dx.doi.org/10.1111/j.1742-7843.2006.00021.xDOI Listing
February 2007

2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4-phenylbutanoyl)pyrrolidines as prolyl oligopeptidase inhibitors.

Bioorg Med Chem 2007 Mar 24;15(5):2024-31. Epub 2006 Dec 24.

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.

In order to replace the P2-P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl-L-Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2-P1 amide group of POP inhibitors can be replaced by an alpha,beta-unsaturated carbonyl group or the aryl conjugated carbonyl group.
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http://dx.doi.org/10.1016/j.bmc.2006.12.036DOI Listing
March 2007

An introduction of a pyridine group into the structure of prolyl oligopeptidase inhibitors.

Bioorg Med Chem Lett 2006 Nov 17;16(21):5590-3. Epub 2006 Aug 17.

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.

A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-l-prolyl group at the P2 position, good lipophilicity can be achieved.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.029DOI Listing
November 2006

Binding kinetics and duration of in vivo action of novel prolyl oligopeptidase inhibitors.

Biochem Pharmacol 2006 Feb 6;71(5):683-92. Epub 2006 Jan 6.

Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, Kuopio FI-70211, Finland.

Prolyl oligopeptidase (POP) is a serine protease that specifically hydrolyses small peptides at the carboxyl end of the proline residue. POP has gained pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties in rat. We examined the effect of the 2(S)-substituents CN and COCH(2)OH at the P1 site of the parent inhibitors isophthalic acid 2(S)-(cyclopentanecarbonyl)pyrrolidine-l-prolyl-pyrrolidine amide and 4-phenylbutanoyl-l-prolyl-pyrrolidine and bulky 5-t-butyl group at the P2 site l-prolyl residue of the parent inhibitor 4-phenylbutanoyl-l-prolyl-pyrrolidine on the binding kinetics to the enzyme. In addition, we studied the duration of POP inhibition in the rat tissues in vivo after i.p. administration. CN and COCH(2)OH substituents at the P1 site pyrrolidine group were found to greatly increase the affinity of the inhibitor and the enzyme-inhibitor complex half-life. In addition, 5-t-butyl group at the P2 site l-prolyl residue increased the dissociation half-life of the enzyme-inhibitor complex, without much affecting the inhibitory potency. The duration of the inhibition in the rat tissues followed the inhibition kinetic properties in that the compounds with fast dissociation produced shorter inhibition in the rat tissues than the compounds with slow dissociation. The duration of POP inhibition of compounds was evidently not governed by their serum clearance. The fact that the in vivo pharmacodynamic behaviour of POP inhibitors can be predicted by their in vitro-properties may be of importance when designing therapeutically useful POP inhibitors.
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http://dx.doi.org/10.1016/j.bcp.2005.11.029DOI Listing
February 2006

Dicarboxylic acid azacycle l-prolyl-pyrrolidine amides as prolyl oligopeptidase inhibitors and three-dimensional quantitative structure-activity relationship of the enzyme-inhibitor interactions.

J Med Chem 2005 Jul;48(15):4772-82

Department of Pharmaceutical Chemistry, P.O. Box 1627, FI-70211 Kuopio, Finland.

A series of dicarboxylic acid azacycle l-prolyl-pyrrolidine amides was synthesized, and their inhibitory activity against prolyl oligopeptidase (POP) from porcine brain was tested. Three different azacycles were tested at the position beyond P3 and six different dicarboxylic acids at the P3 position. l-Prolyl-pyrrolidine and l-prolyl-2(S)-cyanopyrrolidine were used at the P2-P1 positions. The IC(50) values ranged from 0.39 to 19000 nM. The most potent inhibitor was the 3,3-dimethylglutaric acid azepane l-prolyl-2(S)-cyanopyrrolidine amide. Molecular docking (GOLD) was used to analyze binding interactions between different POP inhibitors of this type and the POP enzyme. The data set consisted of the novel inhibitors, inhibitors published previously by our group, and well-known reference compounds. The alignments were further analyzed using comparative molecular similarity indices analysis. The binding of the inhibitors was consistent at the P1-P3 positions. Beyond the P3 position, two different binding modes were found, one that favors lipophilic structures and one that favors nonhydrophobic structures.
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http://dx.doi.org/10.1021/jm0500020DOI Listing
July 2005

A cyclopent-2-enecarbonyl group mimics proline at the P2 position of prolyl oligopeptidase inhibitors.

J Med Chem 2004 Nov;47(23):5605-7

Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland.

With the aim to replace the natural amino acid proline by a proline mimetic structure, a cyclopent-2-enecarbonyl moiety was studied at the P2 position of prolyl oligopeptidase (POP) inhibitors. The cyclopent-2-enecarbonyl moiety proved to be an excellent proline mimetic at the P2 position of POP inhibitors. The replacement is particularly useful when increased lipophilicity is needed.
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http://dx.doi.org/10.1021/jm049503wDOI Listing
November 2004

Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site.

Biochem J 2004 Sep;382(Pt 3):1003-8

Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.

POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH(2)OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (K(i)=11.8-0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, k(on)=(2.43+/-0.12) x 10(5) M(-1) x s(-1), whereas the inhibitor with a CN group exhibited the fastest binding, k(on)=(12.0+/-0.08)x10(5) M(-1) x s(-1). In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH(2)OH and CHO groups had much longer half-lives of dissociation (over 5 h) compared with the compound with the CN group (25 min), although the K(i) values of the compounds were relatively similar. A possibility to optimize the duration of inhibition by changing the functional group at the P1 site is important when planning therapeutically useful POP inhibitors.
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http://dx.doi.org/10.1042/BJ20040992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133977PMC
September 2004

New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides.

J Med Chem 2003 Oct;46(21):4543-51

Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.
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http://dx.doi.org/10.1021/jm030811oDOI Listing
October 2003

Conformationally rigid N-acyl-5-alkyl-L-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors.

Bioorg Med Chem 2003 Aug;11(17):3611-9

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland.

In the N-acyl-L-prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the L-prolyl group was replaced by different 5-alkyl-L-prolyl groups, resulting in a series of N-acyl-5-alkyl-L-prolyl-pyrrolidines. Since N-amides of 5-alkyl-L-prolines are conformationally more rigid than those of L-proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly. A similar effect was not observed for the 5(S)-tert-butyl group. In the series of compounds where the N-acyl group was a 4-phenylbutanoyl group, the 5(R)-tert-butyl, 5(R)-methyl and 5(S)-methyl groups did not have an effect on the potency [the 5(S)-tert-butyl group was not tested in this series]. As an additional effect, the 5-tert-butyl groups increased the log P of the compounds 1.5 log units, which might be beneficial when targeting the compounds to the brain.
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http://dx.doi.org/10.1016/s0968-0896(03)00363-8DOI Listing
August 2003
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