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Claudiu T. Supuran - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure and bioactivity of primary Sulfamate containing natural products
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Prashant Mujumdar, Claudiu T. Supuran, Silvia Bua, Thomas S Peat, Sallyann PoulsenAbstract:Abstract Here we report the synthesis of natural products (NPs) 5′-O-sulfamoyl adenosine 1 and 5′-O-sulfamoyl-2-chloroadenosine 2. As primary Sulfamates these compounds represent an uncommon class of NPs, furthermore there are few NPs known that contain a N S bond. Compounds 1 and 2 were evaluated for inhibition of carbonic anhydrases (CA), a metalloenzyme family where the primary Sulfamate is known to coordinate to the active site zinc and form key hydrogen bonds with adjacent CA active site residues. Both NPs were good to moderate CA inhibitors, with compound 2 a 20–50-fold stronger CA inhibitor (Ki values 65–234 nM) than compound 1. The protein X-ray crystal structures of 1 and 2 in complex with CA II show that it is not the halogen-hydrophobic interactions that give compound 2 a greater binding energy but a slight movement in orientation of the ribose ring that allows better hydrogen bonds to CA residues. Compounds 1 and 2 were further investigated for antimicrobial activity against a panel of microbes relevant to human health, including Gram-negative bacteria (4 strains), Gram-positive bacteria (1 strain) and yeast (2 strains). Antimicrobial activity and selectivity was observed. The minimum inhibitory concentration (MIC) of NP 1 was 10 µM against Gram-positive Staphylococcus aureus and NP 2 was 5 µM against Gram-negative Escherichia coli. This is the first time that NP primary Sulfamates have been assessed for inhibition and binding to CAs, with systematic antimicrobial activity studies also reported.
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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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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.
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mapping selective inhibition of the cancer related carbonic anhydrase ix using structure activity relationships of glucosyl based Sulfamates
Journal of Medicinal Chemistry, 2015Co-Authors: Brian P Mahon, Daniela Vullo, Claudiu T. Supuran, Carrie L Lomelino, Janina Ladwig, Gregory M Rankin, Jenna M Driscoll, Antonieta L Salguero, Melissa A Pinard, Sallyann PoulsenAbstract:Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl Sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 A or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl Sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically “map” key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.
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Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure–Activity Relationships of Glucosyl-Based Sulfamates
2015Co-Authors: Brian P. Mahon, Daniela Vullo, Claudiu T. Supuran, Carrie L Lomelino, Janina Ladwig, Gregory M Rankin, Jenna M Driscoll, Antonieta L Salguero, Melissa A Pinard, Sallyann PoulsenAbstract:Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl Sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl Sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically “map” key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors
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.
Atul Purohit - One of the best experts on this subject based on the ideXlab platform.
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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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synthesis antitubulin and antiproliferative sar of analogues of 2 methoxyestradiol 3 17 o o bis Sulfamate
Journal of Medicinal Chemistry, 2010Co-Authors: Fabrice Jourdan, Mathew P. Leese, Eric Ferrandis, Simon P. Newman, Atul Purohit, M J Reed, Wolfgang Dohle, Ernest Hamel, Barry V L PotterAbstract:The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-Sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-Sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.
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chiral aromatase and dual aromatase steroid sulfatase inhibitors from the letrozole template synthesis absolute configuration and in vitro activity
Journal of Medicinal Chemistry, 2008Co-Authors: Paul M Wood, Atul Purohit, L Lawrence W Woo, M J Reed, Jeanrobert Labrosse, Melanie Trusselle, Sergio Abbate, Giovanna Longhi, Ettore Castiglioni, Barry V L PotterAbstract:To explore aromatase inhibition and to broaden the structural diversity of dual aromatase−sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-Sulfamates or mono-Sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, (R)-phenol (39a) was the most potent aromatase inhibitor (IC50 = 0.6 nM, comparable to letrozole), whereas the (S)-Sulfamate, (40b) inhibited STS most potently (IC50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by...
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2 substituted estradiol bis Sulfamates multitargeted antitumor agents synthesis in vitro sar protein crystallography and in vivo activity
Journal of Medicinal Chemistry, 2006Co-Authors: Mathew P. Leese, Simon P. Newman, Atul Purohit, Michael J. Reed, Bertrand Leblond, Claudiu T. Supuran, Andrew Smith, Anna Di Fiore, Giuseppina De Simone, Barry V L PotterAbstract:The anticancer activities and SARs of estradiol-17-O-Sulfamates and estradiol 3,17-O,O-bis-Sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-Sulfamates 20 and 21, in contrast to the 17-O-monoSulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18−87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-Sulfamate of 21 to the active site zinc and a probable additional l...
Eric Ferrandis - One of the best experts on this subject based on the ideXlab platform.
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quinazolinone based anticancer agents synthesis antiproliferative sar antitubulin activity and tubulin co crystal structure
Journal of Medicinal Chemistry, 2018Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Fabrice Jourdan, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl Sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its Sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone Sulfamates surprisingly showed we...
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Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
2017Co-Authors: Wolfgang Dohle, Philip G. Kasprzyk, Mark P. Thomas, Gregory Menchon, Andrea E Prota, Paul A Foster, Pascoe Mannion, Ernest Hamel, Fabrice L. Jourdan, Eric FerrandisAbstract:Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl Sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure–activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its Sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone Sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template
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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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synthesis antitubulin and antiproliferative sar of analogues of 2 methoxyestradiol 3 17 o o bis Sulfamate
Journal of Medicinal Chemistry, 2010Co-Authors: Fabrice Jourdan, Mathew P. Leese, Eric Ferrandis, Simon P. Newman, Atul Purohit, M J Reed, Wolfgang Dohle, Ernest Hamel, Barry V L PotterAbstract:The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-Sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-Sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.
Mathew P. Leese - One of the best experts on this subject based on the ideXlab platform.
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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.
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synthesis antitubulin and antiproliferative sar of analogues of 2 methoxyestradiol 3 17 o o bis Sulfamate
Journal of Medicinal Chemistry, 2010Co-Authors: Fabrice Jourdan, Mathew P. Leese, Eric Ferrandis, Simon P. Newman, Atul Purohit, M J Reed, Wolfgang Dohle, Ernest Hamel, Barry V L PotterAbstract:The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-Sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-Sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.
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2 substituted estradiol bis Sulfamates multitargeted antitumor agents synthesis in vitro sar protein crystallography and in vivo activity
Journal of Medicinal Chemistry, 2006Co-Authors: Mathew P. Leese, Simon P. Newman, Atul Purohit, Michael J. Reed, Bertrand Leblond, Claudiu T. Supuran, Andrew Smith, Anna Di Fiore, Giuseppina De Simone, Barry V L PotterAbstract:The anticancer activities and SARs of estradiol-17-O-Sulfamates and estradiol 3,17-O,O-bis-Sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-Sulfamates 20 and 21, in contrast to the 17-O-monoSulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18−87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-Sulfamate of 21 to the active site zinc and a probable additional l...
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2-Substituted estradiol Sulfamates: D-ring SAR and anti-tumor activity
Cancer Research, 2006Co-Authors: Mathew P. Leese, Philip G. Kasprzyk, Simon P. Newman, Atul Purohit, Michael J. Reed, Fabrice L. Jourdan, Barry Victor Lloyd PotterAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 1114 Recent studies have demonstrated the multi-mechanism anti-tumor effects of 2-substituted estradiol bis -Sulfamates and highlighted a number of potential advantages that such compounds possess relative to the corresponding estradiols, which include 2-methoxyestradiol (2-MeOE2, Panzem ™) a drug in Phase II clinical trials. 2-Methoxy- (2-MeOE2 bis MATE, STX140, 1) and 2-ethyl-estradiol bis -Sulfamate (2-EtE2 bis MATE, STX243, 2) display potent anti-proliferative and anti-angiogenic activity and also function as inhibitors of steroid sulphatase (STS), a clinical target for the treatment of hormone dependent breast cancer. In order to generate novel agents with anti-proliferative activity against human breast cancer cells we have synthesised a number of 2-substituted estradiol 3- O -Sulfamate analogues with oxygenated side chains tethered at C-17 as bio-isosteric replacements of the 17- O -Sulfamate group of the bis MATEs. The 17β-(2-hydroxyethyl) compound 3 in which the hydroxyl group can function as both hydrogen bond donor or acceptor displays excellent activity against the proliferation of MCF-7 cells (GI50 10 μM) and Sulfamate 5 (GI50 5.6 μM), were relatively inactive. The ethyl ester 6 also displayed only modest activity (GI50 4.2 μM) whilst the analogous keto compound 7 (GI50 0.32 μM) proved to be a suitable bio-isostere for the 17- O -Sulfamate. The simple 17- O -methoxyethyl ether 8 (GI50 0.52 μM) also showed good activity against the proliferation of MCF-7 cells. We have thus synthesised a number of novel D-ring modified 2-substituted estradiol-3- O -Sulfamates with promising in vitro activity, and confirmed both the importance of H-bond acceptor interactions around the D-ring and the steric demands of the site of action. The potential of the sulfamoylated estradiol derivatives for development as anti-cancer agents was reinforced by the activity of 2-EtE2 bis MATE 2 in a MDA-MB-231 xenograft model in female athymic nude mice. An oral dose of the 2 at 40 mg/kg (28d) caused regression and prolonged inhibition of tumour growth that continued after cessation of dosing (6/6 animals) and tumour disappearance (1/6 animals) with no observed toxicity. ![Figure][1] [1]: pending:yes
