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Start Over Author "Simeoni, S." Journal journal of medicinal chemistry
6 results on '"Simeoni, S."'

1. Design, Synthesis, and Biological Evaluation of Sirtinol Analogues as Class III Histone/Protein Deacetylase (Sirtuin) Inhibitors

Author

Mai, A., Massa, S., Lavu, S., Pezzi, R., Simeoni, S., Ragno, R., Mariotti, F. R., Chiani, F., Camilloni, G., and Sinclair, D. A.

Abstract

In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2‘-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3−13 times less potent than sirtinol, whereas the 2‘-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.

Published
2005

2. Class II (IIa)-Selective Histone Deacetylase Inhibitors. 1. Synthesis and Biological Evaluation of Novel (Aryloxopropenyl)pyrrolyl Hydroxyamides

Author

Mai, A., Massa, S., Pezzi, R., Simeoni, S., Rotili, D., Nebbioso, A., Scognamiglio, A., Altucci, L., Loidl, P., and Brosch, G.

Abstract

Chemical manipulations performed on aroyl-pyrrolyl-hydroxyamides (APHAs) led to (aryloxopropenyl)pyrrolyl hydroxamates 2a−w, and their inhibition against maize HDACs and their class I or class II HDAC selectivity were determined. In particular, from these studies some benzene meta-substituted compounds emerged as highly class II (IIa)-selective HDAC inhibitors, the most selective being the 3-chloro- and 3-fluoro-substituted compounds 2c (SI = 71.4) and 2f (SI = 176.4). The replacement of benzene with a 1-naphthyl ring afforded 2s, highly active against the class II homologue HD1-A (IC50 = 10 nM) but less class II-selective than 2c,f. When tested against human HDAC1 and HDAC4, 2f showed no inhibitory activity against HDAC1 but was able to inhibit HDAC4. Moreover, in human U937 acute myeloid leukaemia cells 2f did not produce any effect on apoptosis, granulocytic differentiation, and the cell cycle, whereas 2s (that retain class I HDAC inhibitory activity) was 2-fold less potent than SAHA used as reference.

Published
2005

3. Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors

Author

Gerald Brosch, Giorgia Botta, Marco Miceli, Angela Nebbioso, Dante Rotili, Silvia Simeoni, Rino Ragno, Lucia Altucci, Antonello Mai, Silvio Massa, Mai, A, Massa, S, Rotili, D, Simeoni, S, Ragno, R, Botta, G, Nebbioso, Angela, Miceli, M, Altucci, Lucia, and Brosch, G.

Subjects
Cyclin-Dependent Kinase Inhibitor p21, medicine.drug_class, Stereochemistry, Antineoplastic Agents, Apoptosis, Histone Deacetylase 1, Hydroxamic Acids, Zea mays, Histone Deacetylases, Histones, chemistry.chemical_compound, Histone H3, Mice, Structure-Activity Relationship, Tubulin, Drug Discovery, medicine, Animals, Humans, Uracil, Cell Proliferation, Hydroxamic acid, Histone deacetylase inhibitor, Cell Cycle, Biological activity, Acetylation, U937 Cells, HDAC4, Histone Deacetylase Inhibitors, Repressor Proteins, Biochemistry, chemistry, Molecular Medicine, Histone deacetylase, Drug Screening Assays, Antitumor, Granulocytes
Abstract

A novel series of compounds containing a uracil moiety as the connection unit between a phenyl/phenylalkyl portion and a N-hydroxy-polymethylenealkanamide or -methylenecinnamylamide group (uracil-based hydroxamic acids, UBHAs) was tested against maize histone deacetylases (HDACs) and mouse HDAC1. Compounds with a phenyl/benzyl ring at the uracil-C6 position and bearing 4-5 carbon units as well as a m- or p-methylenecinnamyl moiety as a spacer were the most potent inhibitors. In cell-based human HDAC1 and HDAC4 assays, the two UBHAs tested inhibited the HDAC1 but not HDAC4 immunoprecipitate activity. When tested in human leukemia U937 cells, some UBHAs produced G1 phase arrest of the cell cycle. Moreover, 1j showed high antiproliferative and dose-dependent granulocytic differentiation properties. The tested UBHAs displayed weak p21WAF1/CIP1 induction in U937 cells, and 1d and 1j showed high histone H3 and alpha-tubulin acetylation effects.

Published
2006

4. Synthesis and biological properties of novel 2-aminopyrimidin-4(3H)-ones highly potent against HIV-1 mutant strains.

Author

Mai A, Artico M, Rotili D, Tarantino D, Clotet-Codina I, Armand-Ugón M, Ragno R, Simeoni S, Sbardella G, Nawrozkij MB, Samuele A, Maga G, and Esté JA

Subjects
Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Cell Line, Drug Resistance, Viral, HIV Reverse Transcriptase genetics, HIV-1 genetics, HIV-1 isolation & purification, Humans, Models, Molecular, Mutation, Protein Binding, Pyrimidines chemistry, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, Pyrimidines chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis
Abstract

Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.

Published
2007
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5. Small molecule inhibitors of histone arginine methyltransferases: homology modeling, molecular docking, binding mode analysis, and biological evaluations.

Author

Ragno R, Simeoni S, Castellano S, Vicidomini C, Mai A, Caroli A, Tramontano A, Bonaccini C, Trojer P, Bauer I, Brosch G, and Sbardella G

Subjects
Amino Acid Sequence, Animals, Aspergillus nidulans enzymology, Benzoates chemical synthesis, Benzoates chemistry, Binding Sites, Catalytic Domain, Databases, Protein, Humans, Ligands, Molecular Sequence Data, Naphthalenes chemistry, Protein Conformation, Quantitative Structure-Activity Relationship, Rats, Sequence Homology, Amino Acid, Sulfonic Acids chemistry, Triazines chemistry, Xanthenes chemistry, Models, Molecular, Naphthalenes chemical synthesis, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases chemistry, Repressor Proteins antagonists & inhibitors, Repressor Proteins chemistry, Sulfonic Acids chemical synthesis, Triazines chemical synthesis, Xanthenes chemical synthesis
Abstract

The screening of the inhibition capabilities of dye-like small molecules from a focused library against both human PRMT1 and Aspergillus nidulans RmtA is reported as well as molecular modeling studies (homology modeling, molecular docking, and 3-D QSAR) of the catalytic domain of the PRMT1 fungal homologue RmtA. The good correlation between computational and biological results makes RmtA a reliable tool for screening arginine methyltransferase inhibitors. In addition, the binding mode analyses of tested derivatives reveal the crucial role of two regions, the pocket formed by Ile12, His13, Met16, and Thr49 and the SAM cisteinic binding site subsite. These regions should be taken into account in the design of novel PRMT inhibitors.

Published
2007
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6. Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors.

Author

Mai A, Massa S, Rotili D, Simeoni S, Ragno R, Botta G, Nebbioso A, Miceli M, Altucci L, and Brosch G

Subjects
Acetylation, Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Cycle drug effects, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p21 biosynthesis, Drug Screening Assays, Antitumor, Granulocytes cytology, Granulocytes drug effects, Histone Deacetylase 1, Histone Deacetylases, Histones metabolism, Humans, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Mice, Repressor Proteins antagonists & inhibitors, Structure-Activity Relationship, Tubulin metabolism, U937 Cells, Uracil pharmacology, Zea mays enzymology, Antineoplastic Agents chemical synthesis, Histone Deacetylase Inhibitors, Hydroxamic Acids chemical synthesis, Uracil analogs & derivatives, Uracil chemical synthesis
Abstract

A novel series of compounds containing a uracil moiety as the connection unit between a phenyl/phenylalkyl portion and a N-hydroxy-polymethylenealkanamide or -methylenecinnamylamide group (uracil-based hydroxamic acids, UBHAs) was tested against maize histone deacetylases (HDACs) and mouse HDAC1. Compounds with a phenyl/benzyl ring at the uracil-C6 position and bearing 4-5 carbon units as well as a m- or p-methylenecinnamyl moiety as a spacer were the most potent inhibitors. In cell-based human HDAC1 and HDAC4 assays, the two UBHAs tested inhibited the HDAC1 but not HDAC4 immunoprecipitate activity. When tested in human leukemia U937 cells, some UBHAs produced G1 phase arrest of the cell cycle. Moreover, 1j showed high antiproliferative and dose-dependent granulocytic differentiation properties. The tested UBHAs displayed weak p21WAF1/CIP1 induction in U937 cells, and 1d and 1j showed high histone H3 and alpha-tubulin acetylation effects.

Published
2006
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