K arbonik anhidrazın pH düzenlenmesi, HCO 3-geri emilimi, CO 2 'in solunumla atılması gibi görevl... more K arbonik anhidrazın pH düzenlenmesi, HCO 3-geri emilimi, CO 2 'in solunumla atılması gibi görevlerinin yanısısıra, hafıza, sinyal prosesleri, uzun dönem sinaptik transformasyon olaylarında önemli rolleri vardır. Yapılan çalışmada, sentetik ürünler olan (Benzofuran-2-il)(3-fenil-3-metilsiklobutil) ketoksim (A), (Benzofuran-2-il)(3-metil-3-mezitilsiklobutil)keton tiyosemikarbazon (T), 1,3-bis(2-klorobenzoil)imidazolin-2-tiyon (B) ve H 2 O 2 'in karbonik anhidraz aktivitesi üzerine erkek Wistar karaciğer, eritrosit, kalp ve böbrek dokularında etkileri incelendi. Bu amaçla, kontrol grubu, her bir sentetik ürün için bir grup, H 2 O 2 grubu ve sentetik ürünler ile H 2 O 2 kombinasyon grupları oluşturuldu. Elde edilen verilerden H 2 O 2 uygulan grupta bütün dokularda karbonik anhidraz aktivitesinde azalma olduğu görüldü. Bununla birlikte A maddesi karaciğerde aktivasyona neden olurken T maddesi eritrosit ve kalp dokularında, B maddesi ise karaciğer ve eritrositlerde aynı etkiyi gösterdi.
with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:
The 2.15 Å resolution crystal structure of arginase from Plasmodium falciparum, the parasite that... more The 2.15 Å resolution crystal structure of arginase from Plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(S)-amino-6boronohexanoic acid (ABH; K d = 11 μM). This is the first crystal structure of a parasitic arginase. Various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies, and to probe the structure and function of two polypeptide insertions unique to malarial arginase: a 74-residue low complexity region contained in loop L2, and a 11-residue segment contained in loop L8. Structural studies indicate that the low complexity region is largely disordered and is oriented away from the trimer interface; its deletion does not significantly compromise enzyme activity. The loop L8 insertion is located at the trimer interface and makes several intra-and intermolecular interactions important for enzyme function. In addition, we also demonstrate that arg-P. berghei sporozoites show significantly decreased liver infectivity in vivo. Therefore, inhibition of malarial arginase may serve as a possible candidate for antimalarial therapy against liver-stage infection, and ABH may serve as a lead for the development of inhibitors. Malaria, an infectious disease caused by a parasitic protozoan, is a serious health threat in developing countries due to its facile transmission by the Anopheles mosquito (1,2). Malaria is currently considered to be eradicated in the US; however, ten species of Anopheles mosquitoes are indigenous to the US, suggesting that malaria acquired in endemic countries can be reintroduced in the US by human travel and propagated by mosquitoes. For example, there were 1,505 cases of malaria diagnosed in the US during 2007, including one transfusion-related case and one fatality (3). Worldwide statistics are significantly more severe, with 243 million cases of malaria being diagnosed and 863,000 deaths resulting in 2008 (primarily children in sub-Saharan Africa) (4). Five species of malaria specifically infect humans: Plasmodium falciparum, vivax, malariae, ovale, and knowlesi; Plasmodium falciparum is the most lethal (5). Since the parasite is capable of developing resistance to drug therapy, combination drug therapies are generally required to circumvent this problem (6,7). ‡ The atomic coordinates of the P. falciparum arginase-ABH complex have been deposited in the Protein Data Bank (www.rcsb.org) with accession code 3MMR.
Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenat... more Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.
... 3) according to the activation mechanism described previously, a free amino or imidazole moie... more ... 3) according to the activation mechanism described previously, a free amino or imidazole moiety acting as a second proton transferring group (besides the imidazole ring from the lead histamine) might positively influence efficacy of the CAAs (Supuran and Scoz-zafava 1999 ...
Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiff... more Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.
Journal of the American Chemical Society, Apr 29, 2006
The synthesis of dendritic dipeptides (4-3,4-3,5-4)12G2-CH2-Boc-L-Tyr-L-Ala-OMe and (4-3, 4-3,5-4... more The synthesis of dendritic dipeptides (4-3,4-3,5-4)12G2-CH2-Boc-L-Tyr-L-Ala-OMe and (4-3, 4-3,5-4)12G2-CH2-Boc-D-Tyr-D-Ala-OMe is described. These dendritic dipeptides self-assemble into porous elliptical and circular columns that in turn self-organize into centered rectangular columnar and hexagonal columnar periodic arrays. The transition from porous elliptical to porous circular columns is mediated in a reversible or irreversible way by the thermal history of the sample. A method to determine the dimensions of hollow elliptical and circular columns by the reconstruction of the small-angle powder X-ray diffractograms of the centered rectangular or hexagonal columnar lattices was elaborated. This technique together with wide-angle X-ray experiments performed on aligned fibers provided access to the structural and retrostructural analysis of elliptical supramolecular pores. This procedure is general and can be adapted for the determination of the dimensions of pores of any columnar shape.
Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering t... more Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)- and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the
Bioorganic & Medicinal Chemistry Letters, Oct 1, 2011
As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report t... more As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report the synthesis and biological evaluation of the trifluoromethylketone analogue of L-arginine, (S)-2amino-8,8,8-trifluoro-7-oxo-octanoic acid (10). While this novel amino acid was initially designed as a potential inhibitor of human arginase I, it exhibits no measurable inhibitory activity against this enzyme. Surprisingly, however, 10 is a potent inhibitor of human histone deacetylase 8, with IC 50 = 1.5 ± 0.2 μM. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC 50 = 110 ± 30 μM. The lack of inhibitory activity against human arginase I may result from unfavorable interactions of the bulky trifluoromethyl group of 10 in the constricted active site. Since the active site of histone deacetylase 8 is less constricted, we hypothesize that it accommodates 10 as the gem-diol, which mimics the tetrahedral intermediate and its flanking transition states in catalysis. Therefore, we suggest that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones.
Immortalization and characterization of human myometrial cells from term-pregnant patients using ... more Immortalization and characterization of human myometrial cells from term-pregnant patients using a telomerase
This manuscript reports the synthesis and the self-assembly of (4-3,4,5-3,5)nG2-CH2-Boc-l-Tyr-l-A... more This manuscript reports the synthesis and the self-assembly of (4-3,4,5-3,5)nG2-CH2-Boc-l-Tyr-l-Ala-OMe dendritic dipeptides (n = 12, 16). These dendritic dipeptides self-assemble both in solution and in solid states into helical porous supramolecular columns that mimic porous transmembrane proteins. These supramolecular assemblies provide also a new class of tubular supramolecular polymers.
Page 1. Supramolecular Chemistry DOI: 10.1002/anie.200501331 The Internal Structure of Helical Po... more Page 1. Supramolecular Chemistry DOI: 10.1002/anie.200501331 The Internal Structure of Helical Pores Self-Assembled from Dendritic Dipeptides is Stereochemically Programmed and Allosterically Regulated** Virgil Percec ...
with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:
Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-argini... more Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to generate L-ornithine and urea. We demonstrate that N-hydroxy-L-arginine (NOHA) binds to this enzyme with K(d)=3.6 microM, and nor-N-hydroxy-L-arginine (nor-NOHA) binds with K(d)=517 nM (surface plasmon resonance) or K(d) approximately 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford
K arbonik anhidrazın pH düzenlenmesi, HCO 3-geri emilimi, CO 2 'in solunumla atılması gibi görevl... more K arbonik anhidrazın pH düzenlenmesi, HCO 3-geri emilimi, CO 2 'in solunumla atılması gibi görevlerinin yanısısıra, hafıza, sinyal prosesleri, uzun dönem sinaptik transformasyon olaylarında önemli rolleri vardır. Yapılan çalışmada, sentetik ürünler olan (Benzofuran-2-il)(3-fenil-3-metilsiklobutil) ketoksim (A), (Benzofuran-2-il)(3-metil-3-mezitilsiklobutil)keton tiyosemikarbazon (T), 1,3-bis(2-klorobenzoil)imidazolin-2-tiyon (B) ve H 2 O 2 'in karbonik anhidraz aktivitesi üzerine erkek Wistar karaciğer, eritrosit, kalp ve böbrek dokularında etkileri incelendi. Bu amaçla, kontrol grubu, her bir sentetik ürün için bir grup, H 2 O 2 grubu ve sentetik ürünler ile H 2 O 2 kombinasyon grupları oluşturuldu. Elde edilen verilerden H 2 O 2 uygulan grupta bütün dokularda karbonik anhidraz aktivitesinde azalma olduğu görüldü. Bununla birlikte A maddesi karaciğerde aktivasyona neden olurken T maddesi eritrosit ve kalp dokularında, B maddesi ise karaciğer ve eritrositlerde aynı etkiyi gösterdi.
with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:
The 2.15 Å resolution crystal structure of arginase from Plasmodium falciparum, the parasite that... more The 2.15 Å resolution crystal structure of arginase from Plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(S)-amino-6boronohexanoic acid (ABH; K d = 11 μM). This is the first crystal structure of a parasitic arginase. Various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies, and to probe the structure and function of two polypeptide insertions unique to malarial arginase: a 74-residue low complexity region contained in loop L2, and a 11-residue segment contained in loop L8. Structural studies indicate that the low complexity region is largely disordered and is oriented away from the trimer interface; its deletion does not significantly compromise enzyme activity. The loop L8 insertion is located at the trimer interface and makes several intra-and intermolecular interactions important for enzyme function. In addition, we also demonstrate that arg-P. berghei sporozoites show significantly decreased liver infectivity in vivo. Therefore, inhibition of malarial arginase may serve as a possible candidate for antimalarial therapy against liver-stage infection, and ABH may serve as a lead for the development of inhibitors. Malaria, an infectious disease caused by a parasitic protozoan, is a serious health threat in developing countries due to its facile transmission by the Anopheles mosquito (1,2). Malaria is currently considered to be eradicated in the US; however, ten species of Anopheles mosquitoes are indigenous to the US, suggesting that malaria acquired in endemic countries can be reintroduced in the US by human travel and propagated by mosquitoes. For example, there were 1,505 cases of malaria diagnosed in the US during 2007, including one transfusion-related case and one fatality (3). Worldwide statistics are significantly more severe, with 243 million cases of malaria being diagnosed and 863,000 deaths resulting in 2008 (primarily children in sub-Saharan Africa) (4). Five species of malaria specifically infect humans: Plasmodium falciparum, vivax, malariae, ovale, and knowlesi; Plasmodium falciparum is the most lethal (5). Since the parasite is capable of developing resistance to drug therapy, combination drug therapies are generally required to circumvent this problem (6,7). ‡ The atomic coordinates of the P. falciparum arginase-ABH complex have been deposited in the Protein Data Bank (www.rcsb.org) with accession code 3MMR.
Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenat... more Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.
... 3) according to the activation mechanism described previously, a free amino or imidazole moie... more ... 3) according to the activation mechanism described previously, a free amino or imidazole moiety acting as a second proton transferring group (besides the imidazole ring from the lead histamine) might positively influence efficacy of the CAAs (Supuran and Scoz-zafava 1999 ...
Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiff... more Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.
Journal of the American Chemical Society, Apr 29, 2006
The synthesis of dendritic dipeptides (4-3,4-3,5-4)12G2-CH2-Boc-L-Tyr-L-Ala-OMe and (4-3, 4-3,5-4... more The synthesis of dendritic dipeptides (4-3,4-3,5-4)12G2-CH2-Boc-L-Tyr-L-Ala-OMe and (4-3, 4-3,5-4)12G2-CH2-Boc-D-Tyr-D-Ala-OMe is described. These dendritic dipeptides self-assemble into porous elliptical and circular columns that in turn self-organize into centered rectangular columnar and hexagonal columnar periodic arrays. The transition from porous elliptical to porous circular columns is mediated in a reversible or irreversible way by the thermal history of the sample. A method to determine the dimensions of hollow elliptical and circular columns by the reconstruction of the small-angle powder X-ray diffractograms of the centered rectangular or hexagonal columnar lattices was elaborated. This technique together with wide-angle X-ray experiments performed on aligned fibers provided access to the structural and retrostructural analysis of elliptical supramolecular pores. This procedure is general and can be adapted for the determination of the dimensions of pores of any columnar shape.
Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering t... more Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)- and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the
Bioorganic & Medicinal Chemistry Letters, Oct 1, 2011
As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report t... more As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report the synthesis and biological evaluation of the trifluoromethylketone analogue of L-arginine, (S)-2amino-8,8,8-trifluoro-7-oxo-octanoic acid (10). While this novel amino acid was initially designed as a potential inhibitor of human arginase I, it exhibits no measurable inhibitory activity against this enzyme. Surprisingly, however, 10 is a potent inhibitor of human histone deacetylase 8, with IC 50 = 1.5 ± 0.2 μM. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC 50 = 110 ± 30 μM. The lack of inhibitory activity against human arginase I may result from unfavorable interactions of the bulky trifluoromethyl group of 10 in the constricted active site. Since the active site of histone deacetylase 8 is less constricted, we hypothesize that it accommodates 10 as the gem-diol, which mimics the tetrahedral intermediate and its flanking transition states in catalysis. Therefore, we suggest that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones.
Immortalization and characterization of human myometrial cells from term-pregnant patients using ... more Immortalization and characterization of human myometrial cells from term-pregnant patients using a telomerase
This manuscript reports the synthesis and the self-assembly of (4-3,4,5-3,5)nG2-CH2-Boc-l-Tyr-l-A... more This manuscript reports the synthesis and the self-assembly of (4-3,4,5-3,5)nG2-CH2-Boc-l-Tyr-l-Ala-OMe dendritic dipeptides (n = 12, 16). These dendritic dipeptides self-assemble both in solution and in solid states into helical porous supramolecular columns that mimic porous transmembrane proteins. These supramolecular assemblies provide also a new class of tubular supramolecular polymers.
Page 1. Supramolecular Chemistry DOI: 10.1002/anie.200501331 The Internal Structure of Helical Po... more Page 1. Supramolecular Chemistry DOI: 10.1002/anie.200501331 The Internal Structure of Helical Pores Self-Assembled from Dendritic Dipeptides is Stereochemically Programmed and Allosterically Regulated** Virgil Percec ...
with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:
Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-argini... more Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to generate L-ornithine and urea. We demonstrate that N-hydroxy-L-arginine (NOHA) binds to this enzyme with K(d)=3.6 microM, and nor-N-hydroxy-L-arginine (nor-NOHA) binds with K(d)=517 nM (surface plasmon resonance) or K(d) approximately 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford
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