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Claudiu T. Supuran - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship with pyrazoline based aromatic Sulfamates as carbonic anhydrase isoforms i ii ix and xii inhibitors synthesis and biological evaluation
European Journal of Medicinal Chemistry, 2019Co-Authors: Davide Moi, Claudiu T. Supuran, Alessio Nocentini, Gianfranco Balboni, Alessandro Deplano, Valentina OnnisAbstract:Abstract Four new series of aromatic Sulfamates were synthesized and investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IX, and XII. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear 3,5-diarylpyrazoline moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Pyrazolines are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The derivatives were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally, hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 0.42–90.1 nM), IX (KIs in the range of 0.72–63.6 nM), and XII (KIs in the range of 0.88–85.2 nM). The best substitution fragments at the pyrazoline ring included for CA II a 4-sulfamic group on the 3-aryl and halogens on the 5-aryl or a methoxy group on the 3-aryl and a 4-sulfamate group on the 5-aryl; for CA IX and CA XII they included the sulfamic group on the 3- or 4-position of the 5-aryl and an electronwithdrawing group on the 4-postion of the 3-aryl ring.
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synthesis and biological evaluation of novel pyrazoline based aromatic Sulfamates with potent carbonic anhydrase isoforms ii iv and ix inhibitory efficacy
Bioorganic Chemistry, 2018Co-Authors: Alessio Nocentini, Davide Moi, Gianfranco Balboni, Severo Salvadori, Valentina Onnis, Claudiu T. SupuranAbstract:Abstract Herein we report the synthesis of a new series of aromatic Sulfamates designed considering the sulfonamide COX-2 selective inhibitors celecoxib and valdecoxib as lead compounds. These latter were shown to possess important human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties, with the inhibition of the tumor-associated isoform hCA IX likely being co-responsible of the celecoxib anti-tumor effects. Bioisosteric substitution of the pyrazole or isoxazole rings from these drugs with the pyrazoline one was considered owing to the multiple biological activities ascribed to this latter heterocycle and paired with the replacement of the sulfonamide of celecoxib and valdecoxib with its equally potent bioisoster sulfamate. The synthesized derivatives were screened for the inhibition of four human carbonic anhydrase isoforms, namely hCA I, II, IV, and IX. All screened Sulfamates exhibited great potency enhancement in inhibiting isoform II and IV, widely involved in glaucoma (KIs in the range of 0.4–12.4 nM and 17.7 and 43.3 nM, respectively), compared to the lead compounds, whereas they affected the tumor-associated hCA IX as potently as celecoxib.
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Special Issue: Sulfonamides
MDPI AG, 2017Co-Authors: Claudiu T. SupuranAbstract:The sulfonamides and their structurally related derivatives, such as the Sulfamates and sulfamides, possess the general formula A-SO2NHR, in which the functional group is either directly bound to an aromatic, heterocyclic, aliphatic, or sugar scaffold (of type A), or appended to such a scaffold via a heteroatom, most frequently oxygen or nitrogen (leading thus to Sulfamates and sulfamides, respectively) [...
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Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets
MDPI AG, 2016Co-Authors: Claudiu T. SupuranAbstract:Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3) × 105 s−1 and kcat/KM values of (4.7–8.5) × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and Sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3–90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2–88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets
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synthesis and carbonic anhydrase i ii ix and xii inhibitory activity of Sulfamates incorporating piperazinyl ureido moieties
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Cenzo Congiu, Gianfranco Balboni, Valentina Onnis, Alessandro Deplano, Mariangela Ceruso, Claudiu T. SupuranAbstract:Abstract A series of Sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 1.0–94.4 nM), IX (KIs in the range of 0.91–36.9 nM), and XII (KIs in the range of 1.0–84.5 nM). The best substitution fragments at the piperazine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl.
Barry V L Potter - One of the best experts on this subject based on the ideXlab platform.
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synthesis and in vitro evaluation of piperazinyl ureido Sulfamates as steroid sulfatase inhibitors
European Journal of Medicinal Chemistry, 2019Co-Authors: Davide Moi, Paul A Foster, Gianfranco Balboni, Valentina Onnis, Alessandro Deplano, Lucy G Rimmer, Alisha Jaffri, Barry V L PotterAbstract:Abstract Two new piperazinyl-ureido single ring aryl sulfamate-based inhibitor series were designed against the emerging oncology drug target steroid sulfatase (STS), for which there are existing potent steroidal and non-steroidal agents in clinical trials. 4-(Piperazinocarbonyl)aminoSulfamates (5–31) were obtained by reacting 4-hydroxyarylamines with phenylchloroformate, subsequent sulfamoylation of the resulting hydroxyarylcarbamates and coupling of the product with 1-substituted piperazines. Pyrimidinyl-piperazinourea Sulfamates (35–42) were synthesized by pyrimidine ring closure of 4-Boc-piperazine-1-carboxamidine with 3-(dimethylamino)propenones, deprotection and coupling with the sulfamoylated building block. Target ureidoSulfamates 5–31 and 35–42 were evaluated both as STS inhibitors in vitro using a lysate of JEG-3 human placenta choriocarcinoma cell line and in a whole cell assay. SAR conclusions were drawn from both series. In series 35–42 the best inhibitory activity is related to the presence of a benzofuryl on the pyrimidine ring. In series 5–31 the best inhibitory activity was shown by the ureas bearing 4-chlorophenyl, 3,4-dichlorophenyl groups or aliphatic chains at the piperazino 4-nitrogen displaying IC50 in the 33–94 nM concentration range. Final optimization to the low nanomolar level was achieved through substitution of the arylsulfamate ring with halogens. Four halogenated arylSulfamates of high potency were achieved and two of these 19 and 20 had IC50 values of 5.1 and 8.8 nM respectively and are attractive for potential in vivo evaluation and further development. We demonstrate the optimization of this new series to low nanomolar potency, employing fluorine substitution, providing potent membrane permeant inhibitors with further development potential indicating piperazinyl-ureido aryl sulfamate derivatives as an attractive new class of STS inhibitors.
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Estrogen O-Sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential.
The Journal of steroid biochemistry and molecular biology, 2015Co-Authors: Mark P. Thomas, Barry V L PotterAbstract:Estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors of steroid sulfatase (STS), an emerging drug target for endocrine therapy of hormone dependent diseases that catalyzes inter alia the hydrolysis of estrone sulfate to estrone. In recent years this has stimulated clinical investigation of the estradiol derivative both as an oral prodrug and its currently ongoing exploration in endometriosis. 2-Substituted steroid sulfamate derivatives show considerable potential as multi-targeting agents for hormone-independent disease, but are also potent STS inhibitors. The steroidal template has spawned nonsteroidal STS inhibitors one of which, Irosustat, has been evaluated clinically in breast cancer, endometrial cancer and prostate cancer and there is potential for innovative dual-targeting approaches. This review surveys the role of estrogen Sulfamates, their analogues and current status.
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synthesis and evaluation of analogues of estrone 3 o sulfamate as potent steroid sulfatase inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: L Lawrence W Woo, Atul Purohit, Bertrand Leblond, Barry V L PotterAbstract:Estrone sulfamate (EMATE) is a potent irreversible inhibitor of steroid sulfatase (STS). In order to further expand SAR, the compound was substituted at the 2- and/or 4-positions and its 17-carbonyl group was also removed. The following general order of potency against STS in two in vitro systems is observed for the derivatives: The 4-NO 2 > 2-halogens, 2-cyano > EMATE (unsubstituted) > 17-deoxyEMATE > 2-NO 2 > 4-bromo > 2-(2-propenyl), 2- n -propyl > 4-(2-propenyl), 4- n -propyl > 2,4-(2-propenyl) = 2,4-di- n -propyl. There is a clear advantage in potency to place an electron-withdrawing substituent on the A-ring with halogens preferred at the 2-position, but nitro at the 4-position. Substitution with 2-propenyl or n -propyl at the 2- and/or 4-position of EMATE, and also removal of the 17-carbonyl group are detrimental to potency. Three cyclic Sulfamates designed are not STS inhibitors. This further confirms that a free or N-unsubstituted sulfamate group (H 2 NSO 2 O–) is a prerequisite for potent and irreversible inhibition of STS as shown by inhibitors like EMATE and Irosustat. The most potent derivative synthesized is 4-nitroEMATE ( 2 ), whose IC 50 s in placental microsomes and MCF-7 cells are respectively 0.8 nM and 0.01 nM.
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structure activity relationships of c 17 substituted estratriene 3 o Sulfamates as anticancer agents
Journal of Medicinal Chemistry, 2011Co-Authors: Fabrice Jourdan, Mathew P. Leese, Eric Ferrandis, Simon P. Newman, Atul Purohit, Wolfgang Dohle, Surinder K Chander, Barry V L PotterAbstract:The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-Sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17β-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity.
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Structures of human carbonic anhydrase II/inhibitor complexes reveal a second binding site for steroidal and nonsteroidal inhibitors.
Biochemistry, 2010Co-Authors: Gyles E. Cozier, Mathew P. Leese, Matthew D. Lloyd, Matthew Douglas Baker, Nethaji Thiyagarajan, K. Ravi Acharya, Barry V L PotterAbstract:Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon dioxide to hydrogen carbonate, and its role in maintaining pH balance has made it an attractive drug target. Steroidal sulfamate esters, inhibitors of the cancer drug target steroid sulfatase (STS), are sequestered in vivo by CA II in red blood cells, which may be the origin of their excellent drug properties. Understanding the structural basis of this is important for drug design. Structures of CA II complexed with 2-methoxyestradiol 3-O-sulfamate (3), 2-ethylestradiol 3,17-O,O-bis(sulfamate) (4), and 2-methoxyestradiol 17-O-sulfamate (5) are reported to 2.10, 1.85, and 1.64 A, respectively. Inhibitor 3 interacts with the active site Zn(II) ion through the 3-O-sulfamate, while inhibitors 4 and 5 bind through their 17-O-sulfamate. Comparison of the IC(50) values for CA II inhibition gave respective values of 56, 662, 2113, 169, 770, and 86 nM for estrone 3-O-sulfamate (1), 2-methoxyestradiol 3,17-O,O-bis(sulfamate) (2), 3, 4, 5, and 5'-((4H-1,2,4-triazol-4-yl)methyl)-3-chloro-2'-cyanobiphenyl-4-yl sulfamate (6), a nonsteroidal dual aromatase-sulfatase inhibitor. Inhibitors 2, 5, and 6 showed binding to a second adjacent site that is capable of binding both steroidal and nonsteroidal ligands. Examination of both IC(50) values and crystal structures suggests that 2-substituents on the steroid nucleus hinder binding via a 3-O-sulfamate, leading to coordination through a 17-O-sulfamate if present. These results underline the influence of small structural changes on affinity and mode of binding, the degree of flexibility in the design of sulfamate-based inhibitors, and suggest a strategy for inhibitors which interact with both the active site and the second adjacent binding site simultaneously that could be both potent and selective.
Neil K Garg - One of the best experts on this subject based on the ideXlab platform.
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Suzuki–Miyaura Cross-Coupling of Aryl Carbamates and Sulfamates: Experimental and Computational Studies
2015Co-Authors: Neil K GargAbstract:The first Suzuki–Miyaura cross-coupling reactions of the synthetically versatile O-aryl carbamate and O-sulfamate groups is described. The transformations utilize the inexpensive, bench-stable catalyst NiCl2(PCy3)2 to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups (EDGs, EWGs) are tolerated, in addition to those that possess ortho substitutents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative additions with carbamates and Sulfamates occur via a five-centered transition state, resulting in the exclusive cleavage of the Ar–O bond. Water is found to stabilize the Ni–carbamate catalyst resting state, and thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of polysubstituted aromatic compounds of natural product and bioactive molecule interest
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ni and fe catalyzed cross coupling reactions of phenol derivatives
Organic Process Research & Development, 2013Co-Authors: Tehetena Mesganaw, Neil K GargAbstract:This review describes our laboratory’s efforts to develop transition metal-catalyzed cross-couplings of several unconventional phenol-based electrophiles. Specifically, we highlight herein the following four key transformations: (a) nickel-catalyzed Suzuki–Miyaura couplings of aryl pivalates, carbamates, and Sulfamates to construct sp2–sp2 C–C bonds; (b) iron-catalyzed Kumada couplings of aryl carbamates and Sulfamates for the assembly of sp2–sp3 C–C bonds; (c) nickel-catalyzed amination reactions of carbamates and Sulfamates to build aryl C–N bonds; and (d) nickel-catalyzed reductive cleavage reactions of aryl carbamates to achieve aryl deoxygenation and a rare method for cine substitution. We expect this review will enable the greater use of unconventional phenol-based cross-coupling electrophiles in industrial settings.
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Iron-catalyzed alkylations of aryl Sulfamates and carbamates.
Organic letters, 2012Co-Authors: Amanda L Silberstein, Stephen D Ramgren, Neil K GargAbstract:The alkylation of aryl Sulfamates and carbamates using iron catalysis is reported. The method constructs sp2–sp3 carbon–carbon bonds and provides synthetically useful yields across a range of substrates (>35 examples). The directing group ability of Sulfamates and carbamates, accompanied by their low reactivity toward conventional cross-couplings, renders these substrates useful for the synthesis of polyfunctionalized arenes.
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suzuki miyaura cross coupling of aryl carbamates and Sulfamates experimental and computational studies
Journal of the American Chemical Society, 2011Co-Authors: Kyle W Quasdorf, Aurora Antoftfinch, Peng Liu, Amanda L Silberstein, Anna Komaromi, Tom Blackburn, Stephen D Ramgren, K N Houk, Victor Snieckus, Neil K GargAbstract:The first Suzuki−Miyaura cross-coupling reactions of the synthetically versatile aryl O-carbamate and O-sulfamate groups are described. The transformations utilize the inexpensive, bench-stable catalyst NiCl2(PCy3)2 to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups are tolerated, in addition to those that possess ortho substituents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative addition with carbamates or Sulfamates occurs via a five-centered transition state, resulting in the exclusive cleavage of the aryl C−O bond. Water is found to stabilize the Ni-carbamate catalyst resting state, which thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the uti...
Nilay Hazari - One of the best experts on this subject based on the ideXlab platform.
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dft investigation of suzuki miyaura reactions with aryl Sulfamates using a dialkylbiarylphosphine ligated palladium catalyst
Organometallics, 2017Co-Authors: Patrick R Melvin, Ainara Nova, David Balcells, Nilay Hazari, Mats TilsetAbstract:Aryl Sulfamates are valuable electrophiles for cross-coupling reactions because they can easily be synthesized from phenols and can act as directing groups for C–H bond functionalization prior to cross-coupling. Recently, it was demonstrated that (1-tBu-Indenyl)Pd(XPhos)Cl (XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) is a highly active precatalyst for room-temperature Suzuki–Miyaura couplings of a variety of aryl Sulfamates. Herein, we report an in-depth computational investigation into the mechanism of Suzuki–Miyaura reactions with aryl Sulfamates using an XPhos-ligated palladium catalyst. Particular emphasis is placed on the turnover-limiting oxidative addition of the aryl sulfamate C–O bond, which has not been studied in detail previously. We show that bidentate coordination of the XPhos ligand via an additional interaction between the biaryl ring and palladium plays a key role in lowering the barrier to oxidative addition. This result is supported by NBO and NCI-Plot analysis on the...
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mechanistic study of an improved ni precatalyst for suzuki miyaura reactions of aryl Sulfamates understanding the role of ni i species
Journal of the American Chemical Society, 2017Co-Authors: Megan Mohadjer Beromi, Ainara Nova, David Balcells, Nilay Hazari, Ann M Brasacchio, Gary W Brudvig, Louise M Guard, David J VinyardAbstract:Nickel precatalysts are potentially a more sustainable alternative to traditional palladium precatalysts for the Suzuki–Miyaura coupling reaction. Currently, there is significant interest in Suzuki–Miyaura coupling reactions involving readily accessible phenolic derivatives such as aryl Sulfamates, as the sulfamate moiety can act as a directing group for the prefunctionalization of the aromatic backbone of the electrophile prior to cross-coupling. By evaluating complexes in the Ni(0), (I), and (II) oxidation states we report a precatalyst, (dppf)Ni(o-tolyl)(Cl) (dppf = 1,1′-bis(diphenylphosphino)ferrocene), for Suzuki–Miyaura coupling reactions involving aryl Sulfamates and boronic acids, which operates at a significantly lower catalyst loading and at milder reaction conditions than other reported systems. In some cases it can even function at room temperature. Mechanistic studies on precatalyst activation and the speciation of nickel during catalysis reveal that Ni(I) species are formed in the catalytic ...
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DFT Investigation of Suzuki–Miyaura Reactions with Aryl Sulfamates Using a Dialkylbiarylphosphine-Ligated Palladium Catalyst
2017Co-Authors: Patrick R. Melvin, Ainara Nova, David Balcells, Nilay Hazari, Mats TilsetAbstract:Aryl Sulfamates are valuable electrophiles for cross-coupling reactions because they can easily be synthesized from phenols and can act as directing groups for C–H bond functionalization prior to cross-coupling. Recently, it was demonstrated that (1-tBu-Indenyl)Pd(XPhos)Cl (XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) is a highly active precatalyst for room-temperature Suzuki–Miyaura couplings of a variety of aryl Sulfamates. Herein, we report an in-depth computational investigation into the mechanism of Suzuki–Miyaura reactions with aryl Sulfamates using an XPhos-ligated palladium catalyst. Particular emphasis is placed on the turnover-limiting oxidative addition of the aryl sulfamate C–O bond, which has not been studied in detail previously. We show that bidentate coordination of the XPhos ligand via an additional interaction between the biaryl ring and palladium plays a key role in lowering the barrier to oxidative addition. This result is supported by NBO and NCI-Plot analysis on the transition states for oxidative addition. After oxidative addition, the catalytic cycle is completed by transmetalation and reductive elimination, which are both calculated to be facile processes. Our computational findings explain a number of experimental results, including why elevated temperatures are required for the coupling of phenyl Sulfamates without electron-withdrawing groups and why aryl carbamate electrophiles are not reactive with this catalyst
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Pd-Catalyzed Suzuki–Miyaura and Hiyama–Denmark Couplings of Aryl Sulfamates
Organic letters, 2016Co-Authors: Patrick R Melvin, Nilay Hazari, Megan Mohadjer Beromi, Hemali P. Shah, Michael WilliamsAbstract:Using a recently discovered precatalyst, the first Pd-catalyzed Suzuki–Miyaura reactions using aryl Sulfamates that occur at room temperature are reported. In complementary work, it is demonstrated that a related precatalyst can facilitate the coupling of aryl silanolates, which are less toxic and reactive nucleophiles than boronic acids with aryl chlorides. By combining our results using modern electrophiles and nucleophiles, the first Hiyama–Denmark reactions using aryl Sulfamates are reported.
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pd catalyzed suzuki miyaura and hiyama denmark couplings of aryl Sulfamates
Organic Letters, 2016Co-Authors: Patrick R Melvin, Nilay Hazari, Megan Mohadjer Beromi, Hemali P. Shah, Michael WilliamsAbstract:Using a recently discovered precatalyst, the first Pd-catalyzed Suzuki–Miyaura reactions using aryl Sulfamates that occur at room temperature are reported. In complementary work, it is demonstrated that a related precatalyst can facilitate the coupling of aryl silanolates, which are less toxic and reactive nucleophiles than boronic acids with aryl chlorides. By combining our results using modern electrophiles and nucleophiles, the first Hiyama–Denmark reactions using aryl Sulfamates are reported.
Jean-yves Winum - One of the best experts on this subject based on the ideXlab platform.
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carbonic anhydrase inhibitors synthesis and inhibition of cytosolic tumor associated carbonic anhydrase isozymes i ii and ix with bis Sulfamates
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Jean-yves Winum, Daniela Vullo, Jean-louis Montero, Andrea Scozzafava, Silvia Pastorekova, Lydia Jakubickova, Jaromir Pastorek, Alessio Innocenti, Claudiu T. SupuranAbstract:A series of bis-Sulfamates incorporating aliphatic, aromatic, or betulinyl moieties in their molecules was obtained by reaction of the corresponding diols/diphenols with sulfamoyl chloride. The library of bis-Sulfamates thus obtained was tested for the inhibition of three physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with K I s in the range of 79 nM–16.45 μM, hCA II with K I s in the range of 6–643 nM, and hCA IX with K I s in the range of 4–5400 nM. Several low nanomolar hCA IX inhibitors were detected, such as 1,8-octylene-bis-sulfamate or 1,10-decylene-bis-sulfamate ( K I s in the range of 4–7 nM), which showed good selectivity ratios (in the range of 3.50–3.85) for hCA IX over hCA II inhibition. The most selective hCA IX inhibitor was phenyl-1,4-dimethylene-bis-sulfamate ( K I of 61.6 nM), which was a 10.43 times better hCA IX than hCA II inhibitor. These derivatives are interesting candidates for the development of novel antitumor therapies targeting hypoxic tumors, since hCA IX is highly overexpressed in such tissues, and its presence is correlated with bad prognosis and unfavorable clinical outcome.
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Therapeutic applications of Sulfamates
Expert Opinion on Therapeutic Patents, 2004Co-Authors: Jean-yves Winum, Jean-louis Montero, Andrea Scozzafava, Claudiu T. SupuranAbstract:Sulfamic acid, a rather simple molecule used widely by medicinal chemists for the design of a host of derivatives with pharmacological applications, may give rise to at least four types of derivatives, the O-substituted-, N-substituted- or di-/tri-substituted Sulfamates, which also show specific biological activities. Sulfamate inhibitors of aminoacyl-tRNA synthetases were reported to constitute a new class of antibiotics, useful in the fight of drug-resistant infections. Antiviral agents incorporating sulfamate moieties have also been obtained: the nucleoside/nucleotide HIV reverse transcriptase inhibitors, and the HIV protease inhibitors. In the increasing armamentarium of anticancer drugs, the Sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatase (STS) and the carbonic anhydrases (CAs). Some STS inhibitors, such as 667COUMATE, might be useful for the treatment of hormone-dependent tumours (breast and prostate cancers). Among the many isozymes ...
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Sulfamates and their therapeutic potential
Medicinal research reviews, 2004Co-Authors: Jean-yves Winum, Jean-louis Montero, Andrea Scozzafava, Claudiu T. SupuranAbstract:Starting from the very simple molecule sulfamic acid, O-substituted-, N-substituted-, or di-/tri-substituted Sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the Sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many Sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three Sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant Sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related Sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some Sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents, which are on one hand due to the relative ease with which such compounds are synthesized, and on the other one, due to the fact that biological activity of most of them is impressive.
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Carbonic Anhydrase Inhibitors: Inhibition of Transmembrane, Tumor-Associated Isozyme IX, and Cytosolic Isozymes I and II with Aliphatic Sulfamates
Journal of medicinal chemistry, 2003Co-Authors: Jean-yves Winum, Daniela Vullo, Angela Casini, Jean-louis Montero, A. Scozzafava, Claudiu T. SupuranAbstract:A series of aliphatic Sulfamates and related derivatives incorporating cyclic/polycyclic (steroidal) moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and, more precisely, of the cytosolic isozymes CA I and II and the transmembrane, tumor-associated isozyme CA IX. The most potent CA I inhibitor was n-tetradecyl sulfamate and some (substituted)benzyl/phenethyl Sulfamates (inhibition constants in the low micromolar range). Against CA II, low nanomolar inhibitors (0.7−3.4 nM) were n-decyl sulfamate and the (substituted)benzyl/phenethyl derivatives mentioned above. Effective CA II inhibition was also observed for the hydroxy/keto derivatives of dehydroepiandrosterone sulfamate. Efficient CA IX inhibitory properties, with inhibition constants in the range of 9−23 nM, were observed for the aliphatic Sulfamates C10−C16 (with the most potent inhibitor being the n-dodecyl derivative) and the (substituted)benzyl/phenethyl Sulfamates. The inhibition...
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carbonic anhydrase inhibitors inhibition of cytosolic isozymes i and ii and transmembrane tumor associated isozyme ix with Sulfamates including emate also acting as steroid sulfatase inhibitors
Journal of Medicinal Chemistry, 2003Co-Authors: Jean-yves Winum, Daniela Vullo, Angela Casini, Jean-louis Montero, A. Scozzafava, Claudiu T. SupuranAbstract:A series of Sulfamates or bis-Sulfamates incorporating aliphatic, aromatic, polycyclic (steroidal), and sugar moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of the cytosolic isozymes CA I and II, and the transmembrane, tumor-associated isozymes CA IX. Some of these compounds were previously reported to act as inhibitors of steroid sulfatases, among which estrone sulfatase (ES) and dehydroepiandrosterone sulfatase (DHEAS) are the key therapeutic targets for estrogen-dependent tumors. Very potent (nanomolar) inhibitors were detected against the three investigated CA isozymes. Best CA I inhibitors were phenylsulfamate and some of its 4-halogeno derivatives, as well as the aliphatic compound n-octyl sulfamate. Against CA II, low nanomolar inhibitors (1.1-5 nM) were phenylsulfamate and some of its 4-halogeno/nitro derivatives, n-octyl sulfamate, and estradiol 3,17β-disulfamate among others. All the investigated Sulfamates showed efficient CA IX inhibitory properties, with inhibition constants in the range of 18-63 nM. The best CA IX inhibitor detected so far was 4-chlorophenylsulfamate. These data are critical for the design of novel antitumor properties, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy. The antitumor properties of the ES/DHEAS inhibitors in clinical trials may on the other hand also be due to their potent inhibitory properties of CA isozymes involved in tumorigenicity, such as CA II and CA IX.
