- Carbonic Anhydrase Glycoinhibitors belonging to the Aminoxysulfonamide Series
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Abstract A general approach for the synthesis of carbonic anhydrases glycoinhibitors belonging to an aminoxysulfonamide series is presented using a Ferrier sulfonamidoglycosylation reaction on glycals. All the compounds showed good in vitro inhibitory activity against four human carbonic anhydrase isoforms, with selectivity against the cytosolic (hCA II) vs the tumor associated (hCA IX and XII) enzymes.
- Ombouma, Joanna,Vullo, Daniella,Dumy, Pascal,Supuran, Claudiu T.,Winum, Jean-Yves
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- Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic N-Sulfonylimines via Palladium-Catalyzed Addition of Arylboronic Acids
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A facile method for kinetic resolution of [2.2]paracyclophane-derived cyclic N-sulfonylimines based on palladium-catalyzed addition of arylboronic acids was developed, giving two kinds of planar chiral [2.2]paracyclophane derivatives in excellent diastereoselectivities and up to 99% of enantioselectivities with high selectivity factors (s up to 128).
- Zhao, Yang,Wang, Xiao-Qing,Yu, Yan-Jiang,Zhou, Yong-Gui
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- Uracil-5-yl O-Sulfamate: An Illusive Radiosensitizer. Pitfalls in Modeling the Radiosensitizing Derivatives of Nucleobases
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Efficient radiotherapy requires the concomitant use of ionizing radiation (IR) and a radiosensitizer. In the present work uracil-5-yl O-sulfamate (SU) is tested against its radiosensitizing potential. The compound possesses appropriate dissociative electron attachment (DEA) characteristics calculated at the M06-2X/6-31++G(d,p) level. Crossed electron-molecular beam experiments in the gas phase demonstrate that SU undergoes efficient DEA processes, and the single C-O or S-O bond dissociations account for the majority of fragments induced by electron attachment. Most DEAs proceed already for electrons with kinetic energies of ～0 eV, which is supported by the exothermic thresholds calculated at the M06-2X/aug-cc-pVTZ level. However, in water solution under reductive conditions and physiological pH, SU does not undergo radiolysis, which demonstrates the crucial influence of aqueous environment on the radiosensitizing properties of modified nucleosides.
- Arthur-Baidoo, Eugene,Chomicz-Mańka, Lidia,Denifl, Stephan,Falkiewicz, Karina,Kozak, Witold,Makurat, Samanta,Rak, Janusz,Rodrigues Costa, Mateus Salomao,Sikorski, Artur,Spisz, Paulina,Wyrzykowski, Dariusz,Zdrowowicz, Magdalena,Ziegler, Patrick
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- Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs
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The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.
- Burke, Eileen G.,Gold, Brian,Hoang, Trish T.,Raines, Ronald T.,Schomaker, Jennifer M.
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- Oxidative Allene Amination for the Synthesis of Azetidin-3-ones
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Regioselectivity in the aziridination of silyl-substituted homoallenic sulfamates is readily diverted to the distal double bond of the allene to yield endocyclic bicyclic methyleneaziridines with excellent stereocontrol. Subsequent reaction with electrophilic oxygen sources initiates facile rearrangement to densely functionalized, fused azetidin-3-ones in excellent d.r., effectively transferring the axial chirality of the allene to central chirality in the products. The steric nature of the silyl group dictates which of the two rings of the fused azetidin-3-one will undergo further functionalization, providing an additional element of diversity for the preparation of enantioenriched azetidine scaffolds with potential biological activity.
- Burke, Eileen G.,Schomaker, Jennifer M.
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- Rhodium(II)-catalyzed alkyne amination of homopropargylic sulfamate esters: Stereoselective synthesis of functionalized norcaradienes by arene cyclopropanation
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A rhodium(II) catalyzed nitrene-alkyne cycloaddition of stereochemically well-defined homopropargylic ethers is followed by arene cyclopropanation to afford unique tetracyclic norcaradiene products bearing a cyclic sulfamate. Products from the arene cyclopropanation (Buchner reaction) can be converted to fused cycloheptatrienes via a ring enlarging electrocyclization after nucleophilic ring opening of the cyclic sulfamate ester.
- Brawn, Ryan A.,Zhu, Kaicheng,Panek, James S.
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- Novel steroid sulfatase inhibitors based on N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates
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In the present work, we described convenient methods for the synthesis of N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC50 value of 0.201 μM (the IC50 value of 667-COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF-7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a-g and their N-phosphorylated analogs 6a-h, whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N-phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667-COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds (6e, 6f, 9b, and 9e) did not exert any toxic effects on zebrafish embryos.
- Da?ko, Mateusz,Demkowicz, Sebastian,Biernacki, Karol,Harrous, Amira,Rachon, Janusz,Kozak, Witold,Martyna, Aleksandra,Mas?yk, Maciej,Kubiński, Konrad,Boguszewska-Czubara, Anna
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- Stereoselective Synthesis of the β-Amino Acid Moiety of Fijiolide A
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An enantioselective synthesis of the β-amino acid moiety of fijiolide A is described. Starting from eugenol, two sulfamates could be obtained on gram scale as substrates for an enantioselective C–H amination using Rh2(R/S-nap)4. Acylation and ring opening of the resulting oxathiazinanes, followed by stepwise oxidation of the corresponding amino alcohol and TES-protection of the catechol gave rise to Cramer's amino acid fragment from the total synthesis of fijiolide A.
- Kurzawa, Timon,Kerste, Eric,Nikodemiak, Paul,Bothe, Daniel,Harms, Klaus,Koert, Ulrich
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- Synthesis of 7-benzylguanosine cap-analogue conjugates for eIF4E targeted degradation
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Eukaryotic translation initiation factor 4E (eIF4E) is a key player in the initiation of cap-dependent translation through recognition of the m7GpppX cap at the 5’ terminus of coding mRNAs. As eIF4E overexpression has been observed in a number of human diseases, most notably cancer, targeting this oncogenic translation initiation factor has emerged as a promising strategy for the development of novel anti-cancer therapeutics. Toward this end, in the present study, we have rationally designed a series of Bn7GxP-based PROTACs for the targeted degradation of eIF4E. Herein we describe our synthetic efforts, in addition to biochemical and cellular characterization of these compounds.
- Kaur, Tanpreet,Menon, Arya,Garner, Amanda L.
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- The Influence of the Counterions [AsF6]– and [GeF6]2– on the Structure of the [ClSO2NH3]+ Cation
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Chlorosulfonamide reacts in the superacidic solutions HF/GeF4 and HF/AsF5 under the formation of ([ClSO2NH3]+)2[GeF6]2– and [ClSO2NH3]+/sup
- Leitz, Dominik,Stierstorfer, Karin,Morgenstern, Yvonne,Zischka, Florian,Kornath, Andreas J.
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- Lewis Base-Br?nsted Acid Co-catalyzed Morita-Baylis-Hillman Reaction of Cyclic Sulfamidate Imines
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A Lewis base-Br?nsted acid co-catalyzed Morita-Baylis-Hillman reaction of cyclic sulfamidate imines with acrylate-type Michael acceptors has been developed. The combination of equimolecular catalytic amounts of DABCO and acetic acid proved highly efficient and tolerated well a wide range of Michael acceptors and substituted 6-membered ring sulfamidate imines, as well as a sultam derivative. The reaction provides a straightforward access to sulfamidates bearing α,β-unsaturated chains, which allows for the further functionalization of the products. Moreover, the robustness and applicability of the method was demonstrated by performing a gram scale reaction and further functionalization of the MBH-adducts.
- García Manche?o, Olga,Khassenova, Gaukhar
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- Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors
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Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNALeu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, Kiapp values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development.
- De Ruysscher, Dries,Pang, Luping,Lenders, Stijn M.G.,Cappoen, Davie,Cos, Paul,Rozenski, Jef,Strelkov, Sergei V.,Weeks, Stephen D.,Van Aerschot, Arthur
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- Gold(I)-Catalyzed Intramolecular Dehydrative Amination of Sulfamate Esters Tethered to Allylic Alcohols: A Strategy for the Synthesis of Cyclic Sulfamidates
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An efficient synthesis protocol for cyclic sulfamidates has been developed via catalytic intramolecular cyclizations of sulfamate esters tethered to allylic alcohols. The reactions proceed smoothly at room temperature in the presence of (IPr)AuCl (5 mol%) and AgBF4 (5 mol%). This protocol features good to excellent yields, high selectivity, broad substrate scope, and mild reaction conditions. This method is also applicable to the synthesis of a seven-membered sulfamidate. (Figure presented.).
- Park, Yunjeong,Lee, Ji Sun,Ryu, Jae-Sang
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supporting information
p. 2183 - 2188
(2021/03/15)
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- MSBA-S – A pentacyclic sulfamate as a new option for radiotherapy of human breast cancer cells
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Many pentacyclic triterpenoids show anti-cancer and anti-inflammatory properties. Recently, we detected a pronounced cytotoxicity and radiosensitivity of two betulinyl sulfamates in human breast cancer cells. Besides betulinic acid scaffold (BSBA-S), we synthesized several new sulfamate-coupled scaffolds from oleanolic acid (OSBA-S), ursolic acid (USBA-S), platanic acid (PSBA-S) and maslinic acid (MSBA-S). Highest cytotoxicity was monitored in breast cancer cell lines after MSBA-S treatment showing in SRB assays IC50 values between 3.7 μM and 5.8 μM. Other sulfamate/triterpene conjugates, however, were less cytotoxic holding IC50 values between 6.6 μM and >50 μM, respectively. MSBA-S-treated breast cancer cells displayed significantly reduced clonogenic survival and an increased rate of apoptosis as compared to the other conjugates. In addition, MSBA-S in combination with irradiation resulted in effects on radiosensitivity in MDA-MB-231 cells (DMF10 = 1.14). In particular, ROS formation was strongly assessed in MSBA-S-treated breast cancer cells. Our findings suggest that the sulfamate derivative of maslinic acid MSBA-S might be a new option for the radiation therapy in breast cancer cells.
- Bache, Matthias,Eiselt, Yvonne,Funtan, Anne,Kahnt, Michael,Paschke, Reinhard,Petrenko, Marina,Serbian, Immo,Vordermark, Dirk,Csuk, René,Güttler, Antje,Ke?ler, Jacqueline,Pflüger, Elena
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- New potent STS inhibitors based on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates
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A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta. We found that compounds substituted with fluorine atom at the meta position demonstrated the highest inhibitory effects in enzymatic STS assay. The most active analog 12e–inhibited STS enzyme with the IC50 value of 36 nM.
- Da?ko, Mateusz,Demkowicz, Sebastian,Rachon, Janusz,Biernacki, Karol,Aszyk, Justyna,Kozak, Witold,Mas?yk, Maciej,Kubiński, Konrad
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p. 1037 - 1044
(2019/12/03)
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- Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors
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Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC50 0.13 μM) and MCF-7 cell lines (IC50 1.35 μM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with KI and kinact value of 86.9 nM and 158.7 min?1, respectively.
- Chang, Chiao-Nien,Chen, Mei-Jou,Chiu, Pei-Fang,Hng, Yue,Liang, Pi-Hui,Lin, I-Chun,Lin, Mei-Hsiang,Lin, Tzung-Sheng,Liu, I-Chen,Lu, Yeh-Lin,Tsai, Keng-Chang
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- Accelerated Reactivity Mechanism and Interpretable Machine Learning Model of N-Sulfonylimines toward Fast Multicomponent Reactions
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We introduce chemical reactivity flowcharts to help chemists interpret reaction outcomes using statistically robust machine learning models trained on a small number of reactions. We developed fast N-sulfonylimine multicomponent reactions for understanding reactivity and to generate training data. Accelerated reactivity mechanisms were investigated using density functional theory. Intuitive chemical features learned by the model accurately predicted heterogeneous reactivity of N-sulfonylimine with different carboxylic acids. Validation of the predictions shows that reaction outcome interpretation is useful for human chemists.
- Jethava, Krupal P.,Fine, Jonathan,Chen, Yingqi,Hossain, Ahad,Chopra, Gaurav
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supporting information
p. 8480 - 8486
(2020/11/18)
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- Catalytic Metal-free Allylic C?H Amination of Terpenoids
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The selective replacement of C?H bonds in complex molecules, especially natural products like terpenoids, is a highly efficient way to introduce new functionality and/or couple fragments. Here, we report the development of a new metal-free allylic amination of alkenes that allows the introduction of a wide range of nitrogen functionality at the allylic position of alkenes with unique regioselectivity and no allylic transposition. This reaction employs catalytic amounts of selenium in the form of phosphine selenides or selenoureas. Simple sulfonamides and sulfamates can be used directly in the reaction without the need to prepare isolated nitrenoid precursors. We demonstrate the utility of this transformation by aminating a large set of terpenoids in high yield and regioselectivity.
- Teh, Wei Pin,Obenschain, Derek C.,Black, Blaise M.,Michael, Forrest E.
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supporting information
p. 16716 - 16722
(2020/11/09)
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- Enantioselective (3+2) cycloaddition: Via N-heterocyclic carbene-catalyzed addition of homoenolates to cyclic N -sulfonyl trifluoromethylated ketimines: Synthesis of fused N-heterocycle γ-lactams
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An enantioselective (3+2) cycloaddition of enals and cyclic N-sulfonyl trifluoromethyl ketimines via N-heterocyclic carbene-catalyzed homoenolate addition is described. This reaction can efficiently construct fused N-heterocycle γ-lactams bearing two adjacent chiral centers with >20?:?1 dr and 94-99% ee, with one chiral center as a trifluoromethylated α-tetrasubstituted carbon stereocenter.
- Zhang, Zhen-Zhen,Zhang, Yongna,Duan, Hui-Xin,Deng, Zhuo-Fei,Wang, You-Qing
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supporting information
p. 1553 - 1556
(2020/02/13)
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- Dissecting modular synthases through inhibition: A complementary chemical and genetic approach
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Modular synthases, such as fatty acid, polyketide, and non-ribosomal peptide synthases (NRPSs), are sophisticated machineries essential in both primary and secondary metabolism. Various techniques have been developed to understand their genetic background and enzymatic abilities. However, uncovering the actual biosynthetic pathways remains challenging. Herein, we demonstrate a pipeline to study an assembly line synthase by interrogating the enzymatic function of each individual enzymatic domain of BpsA, a NRPS that produces the blue 3,3′-bipyridyl pigment indigoidine. Specific inhibitors for each biosynthetic domain of BpsA were obtained or synthesized, and the enzymatic performance of BpsA upon addition of each inhibitor was monitored by pigment development in vitro and in living bacteria. The results were verified using genetic mutants to inactivate each domain. Finally, the results complemented the currently proposed biosynthetic pathway of BpsA.
- Vickery, Christopher R.,McCulloch, Ian P.,Sonnenschein, Eva C.,Beld, Joris,Noel, Joseph P.,Burkart, Michael D.
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supporting information
(2019/12/24)
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- Synthesis of chiral a-substituted a-amino acid and amine derivatives through Ni-catalyzed asymmetric hydrogenation
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Highly efficient Ni-catalyzed asymmetric hydrogenation of cyclicN-sulfonyl ketimino esters was, for the first time, successfully developed, providing various chiral a-monosubstituted a-amino acid derivatives with excellent results (97-99% yields, 90 to >99% ee). CyclicN-sulfonyl ketimines were also hydrogenated well to afford chiral amine derivatives with 98-99% yields and 97 to >99% ee. The gram-scale asymmetric hydrogenation was performed well with 85% yield and 99% ee using only 0.2 mol% catalyst.
- Cong, Hengjiang,Dong, Xiu-Qin,Liu, Gongyi,Wang, Heng,Zhang, Xianghe,Zhang, Xumu
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supporting information
p. 4934 - 4937
(2020/05/13)
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- Gram-scale preparation of the antibiotic lead compound salicyl-AMS, a potent inhibitor of bacterial salicylate adenylation enzymes
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Salicyl-AMS (1) is a potent inhibitor of salicylate adenylation enzymes used in bacterial siderophore biosynthesis and a promising lead compound for the treatment of tuberculosis. An optimized, multigram synthesis is presented, which provides salicyl-AMS as its sodium salt (1·Na) in three synthetic steps followed by a two-step salt formation process. The synthesis proceeds in 11.6% overall yield from commercially available adenosine 2′,3′-acetonide and provides highly purified material.
- Kinarivala, Nihar,Standke, Lisa C.,Guney, Tezcan,Ji, Cheng,Noguchi, Naoyoshi,Asano, Yasutomi,Tan, Derek S.
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- Efficient visible-light photocatalytic aerobic oxidation of cyclic sulfamides to imines
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A highly efficient photocatalytic aerobic oxidation of cyclic sulfamides to synthesize cyclic N-sulfonyl imines with Ir(ppy)2(dtbpy)PF6 as photocatalyst is reported. These environmentally friendly transformations exihibit good to excellent isolated yields and good generality with respect to both five-membered and six-membered cyclic sulfamides.
- Ming, Zong-Yao,Li, Kang-Rui,Meng, Fan-Jie,Shi, Lei,Jiang, Wen-Feng
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supporting information
(2020/06/17)
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- Synthesis of chiral quaternary fluorinated cyclic sulfamidates via palladium-catalyzed arylation with arylboronic acids
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An enantioselective palladium-catalyzed arylation of fluorinated cyclic N-sulfonyl ketimines with arylboronic acids is described. This methodology provides an efficient and convenient route to chiral quaternary fluorinated cyclic sulfamidates in high yields with up to 99% ee.
- Chen, Mu-Wang,Mao, Xuechun,Ji, Yue,Yuan, Jianjun,Deng, Zhihong,Peng, Yiyuan
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supporting information
(2019/11/13)
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- Preparation method of sulfamic acid methyl ester
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The invention discloses a preparation method of sulfamic acid methyl ester. The preparation method comprises following steps: 1, chlorosulfonyl isocyanate is introduced into a reaction container, nitrogen gas protection is adopted, stirring is carried out, the temperature is reduced through cooling to -15 to -10 DEG C, formic acid is added drop by drop so as to obtain chlorosulfonamide; 2, chlorosulfonamide, a reaction solvent, and 4-dimethylaminopyridine are introduced into another reaction container, nitrogen gas protection is adopted, cooling is carried out, the temperature is reduced through cooling to -5 to 0 DEG C, methanol and an organic base are added drop by drop, after adding, stirring reaction is carried out, and a silica gel column is adopted for chromatography purification so as to obtain a finished product. The preparation method are simple in steps, and low in cost, and are suitable for large scale preparation. The content of prepared sulfamic acid methyl ester is 97.0% or higher, yield is 70% or higher, theory base is provided for medicine safe using, effective data support is provided for quality standards of medicines such as cefoxitin, and effective guarantee is provided for medicine safe clinical using.
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Paragraph 0027; 0029-0031; 0035; 0037-0039; 0043; 0045-0047
(2019/10/01)
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- Regio- and Diastereoselective Access to 4-Imidazolidinones via an Aza-Mannich Initiated Cyclization of Sulfamate-Derived Cyclic Imines with α-Halo Hydroxamates
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An efficient regio- and diastereoselective cyclization of sulfamate-derived cyclic imines with unsubstituted or monosubstituted α-halo hydroxamates is developed under mild conditions. This reaction proceeds smoothly under transition-metal-free conditions via a domino aza-Mannich addition/intramolecular nucleophilic substitution sequence, providing a convenient route to access 2-monosubstituted and 2,5-disubstituted 4-imidazolidinones. Notably, the products were obtained with single trans-isomers in moderate to excellent yields.
- Zhou, Jing,Zhang, Hong,Chen, Xue-Lian,Qu, Ya-Li,Zhu, Qianqian,Feng, Chen-Guo,Chen, Ya-Jing
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p. 9179 - 9187
(2019/08/12)
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- Discovery of coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents
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The burst of reactive oxygen species (ROS) contributes to and exacerbates cardiac injury. Exogenous supplementation of antioxidants or upregulation of endogenous antioxidant defense genes should be the potential therapies for cardiovascular disease. Sixteen coumarin-derived imino sulfonates compounds were synthesized with the ability of attenuating oxidative stress directly by reducing intracellular ROS level via promoting Nrf2 pathway. The cell-based assays showed that most of the compounds had significant protective activity against H2O2-induced oxidative injury in H9c2 cells. Compound 5h with the highest activity and low cytotoxicity was demonstrated to remarkably remove the intracellular ROS accumulation by activating expressions of Nrf2 and its downstream antioxidant proteins (ie. HO-1 and NQO1), indicating a novel promising antioxidant and Nrf2 activator. Overall, these findings demonstrated that compound 5h could serve as a potential cardioprotective agent. Moreover, our study features developing new antioxidants and Nrf2 activators by introducing a sulfonyl group and nitrogen atom to the α,β-unsaturated carbonyl entity in coumarin, rather than adding new functional groups or active fragments to coumarin itself.
- Wei, Bo,Zhou, Jing,Xu, Jia-Jia,Cui, Jing,Ping, Feng-Feng,Ling, Jing-Jing,Chen, Ya-Jing
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- Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase
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Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these bacterial targets.
- Cain, Ricky,Salimraj, Ramya,Punekar, Avinash S.,Bellini, Dom,Fishwick, Colin W. G.,Czaplewski, Lloyd,Scott, David J.,Harris, Gemma,Dowson, Christopher G.,Lloyd, Adrian J.,Roper, David I.
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supporting information
p. 9703 - 9717
(2019/11/13)
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- Synthesis and evaluation of coumate analogues as estrogen receptor inhibitors for breast cancer therapy
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A sulphatase inhibitor 667 COUMATE is in clinical trials for estrogen-positive breast cancer therapy for postmenopausal women, while there are a number of similar sulphataseinbitors are under development. Schiff’s bases are versatile pharmacophores in which the N atom involves in hydrogen bonding with active cell centers interfering in normal cell biology. A library of novel coumate analogues with Schiff bases were designed, and structural based drug design was performed with human estrogen receptor (PDB ID: 2IOG) (Already reported). Based on the in-silico outcomes, seven coumate-schiff bases were synthesized. The compounds were obtained in good yield. The novelty had been ascertained by sci?inder software. The synthesized molecules were consistent with their assigned spectra such as IR, Mass and NMR spectral data which con?irmed their formation. The cytotoxicity study was performed by MTT assay for all the synthesized compounds. Most of the compounds have good IC50 values (below 100 μg/ml).Two of the synthesized compounds COU2 and COU-5 have shown good IC50 values such as 19μg/ml and 39μg/ml, respectively. They suppressed the proliferation of estrogen receptor overexpressed MCF-7 cells.
- Jubie, Selvaraj,Basheer,Yadav, Neetu,Wadhwani, Ashish,Afzal Azam, Mohammed
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p. 2218 - 2224
(2019/10/22)
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- Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from Cyclic Imines and Vinyl Aziridines
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The synthesis of cyclic imidazolidines via two N-C bond-forming sequences has been developed. The transformation goes through a (3 + 2)-cycloaddition reaction in the presence of catalytic amounts of palladium by combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly, the use of LiCl as additive allowed the improvement of diastereoselectivities when less encumbered substrates were used. The imidazolidine derivatives that bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and diastereoselectivities (up to >20:1).
- Spielmann, Kim,Lee, Arie Van Der,De Figueiredo, Renata Marcia,Campagne, Jean-Marc
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supporting information
p. 1444 - 1447
(2018/03/09)
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- Enantioselective Construction of Tetrahydroquinazoline Motifs via Palladium-Catalyzed [4 + 2] Cycloaddition of Vinyl Benzoxazinones with Sulfamate-Derived Cyclic Imines
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A palladium-catalyzed enantioselective [4 + 2] cycloaddition reaction of vinyl benzoxazinones with sulfamate-derived cyclic imines is described, affording the tetrahydroquinazolines bearing several functional rings in high yields (up to 99% yield) with good to excellent diastereoselectivities and excellent enantioselectivities (up to 96% ee). This reaction represents the first Pd-catalyzed asymmetric decarboxylative cycloaddition of vinyl benzoxazinones with imines.
- Wang, Chang,Li, Yan,Wu, Yang,Wang, Qijun,Shi, Wangyu,Yuan, Chunhao,Zhou, Leijie,Xiao, Yumei,Guo, Hongchao
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supporting information
p. 2880 - 2883
(2018/05/29)
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- Family-wide analysis of aminoacyl-sulfamoyl-3-deazaadenosine analogues as inhibitors of aminoacyl-tRNA synthetases
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Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N3-position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs). A typical organism has 20 different aaRS, which can be split into two distinct structural classes. We therefore coupled six different amino acids, equally targeting the two enzyme classes, via the sulfamate bridge to 3-deazaadenosine. Upon evaluation of the inhibitory potency of the obtained analogues, a clear class bias was noticed, with loss of activity for the aaS3DA analogues targeting class II enzymes when compared to the equivalent aaSA. Evaluation of the available crystallographic structures point to the presence of a conserved water molecule which could have importance for base recognition within class II enzymes, a property that can be explored in future drug design efforts.
- Zhang, Baole,De Graef, Steff,Nautiyal, Manesh,Pang, Luping,Gadakh, Bharat,Froeyen, Matheus,Van Mellaert, Lieve,Strelkov, Sergei V.,Weeks, Stephen D.,Van Aerschot, Arthur
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p. 384 - 396
(2018/02/27)
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- SULFAMIDE AND SULFAMATE INHIBITORS OF hHint1
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Embodiments provide, among things, compounds of the formula I and methods for using such compounds to reduce pain (e.g., neuronal pain), treat a mammal's addiction to nicotine or anti-pain drugs, and increase a mammal's sensitivity to drugs that bind MOR or NMDAR.
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Paragraph 0125
(2018/03/25)
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- Synthesis, structure and bioactivity of primary sulfamate-containing natural products
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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.
- Mujumdar, Prashant,Bua, Silvia,Supuran, Claudiu T.,Peat, Thomas S.,Poulsen, Sally-Ann
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supporting information
p. 3009 - 3013
(2018/04/30)
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- Palladium(0)-Catalyzed Diastereoselective (3+2) Cycloadditions of Vinylcyclopropanes with Sulfonyl-Activated Imines
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We report herein a palladium(0)-catalyzed (3+2)-cycloaddition process between vinylcyclopropanes and cyclic or acyclic sulfonylimines. This reaction, which operates under low catalyst loading and practical reaction conditions, gives access to a wide variety of N-heterocyclic derivatives in good to excellent yields and high levels of diastereoselectivity.
- Ling, Johanne,Laugeois, Maxime,Ratovelomanana-Vidal, Virginie,Vitale, Maxime R.
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supporting information
p. 2288 - 2292
(2018/10/20)
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- BIARYL KINASE INHIBITORS
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The present disclosure is directed to biaryl compounds of formula (I) which can inhibit AAKl (adaptor associated kinase 1), compositions comprising such compounds and their use for treating e.g. pain, Alzheimer's disease, Parkinson's disease and schizophrenia.
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Page/Page column 65; 66
(2017/05/07)
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- Synthesis and biological evaluation of N-acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors
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Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un-sulfated forms and promotes the growth of various hormone-dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid-sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N-acylated tyramines that contain C–F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4-(2-perfluoroundecanoylaminoethyl)-phenyl sulfamate, 5r, demonstrated the greatest inhibitory effect, with an IC50 value of 2.18?μm (IC50 value of 2.13?μm for coumarin-7-O-sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.
- Da?ko, Mateusz,Rachon, Janusz,Mas?yk, Maciej,Kubiński, Konrad,Demkowicz, Sebastian
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p. 156 - 161
(2017/06/19)
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- Synthetic Study on Pactamycin: Stereoselective Synthesis of the Cyclopentane Core Framework
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The cyclopentane core framework 23 of pactamycin (1) was synthesized in 14 steps from symmetric cyclohexadiene 11. Our synthetic strategy features Rh-mediated catalytic desymmetrization of 10 via aziridination and then regioselective ring-opening reaction
- Goto, Atsumi,Yoshimura, Satoshi,Nakao, Yuta,Inai, Makoto,Asakawa, Tomohiro,Egi, Masahiro,Hamashima, Yoshitaka,Kondo, Mitsuru,Kan, Toshiyuki
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supporting information
p. 3358 - 3361
(2017/07/15)
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- Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors
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In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta and against estrogen receptor-(ER)-positive MCF-7 and T47D cells, as well as ER-negative MDA-MB-231 and SkBr3 cancer cell lines. In the course of our investigation, compounds 6c and 6j demonstrated the highest inhibitory effect in enzymatic STS assays, both with IC50values of 0.18?μM (the IC50value of coumarin-7-O-sulfamate is 1.38?μM, used as a reference). Compound 6j exhibited the highest potency against the MCF-7 and T47D cell lines (15.9?μM and 8.7?μM, respectively). The GI50values of tamoxifen (used as a reference) were 6.8; 10.6; 15.1; 12.5?μM against MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines, respectively. Despite the slightly lower activity of compounds 1 and 2 (both in enzymatic and cell-based experiments) compared to 6g and 6j, analogues 1 and 2 proved to selectively inhibit the growth of ER- and PR-positive cell lines.
- Da?ko, Mateusz,Przyby?owska, Maja,Rachon, Janusz,Mas?yk, Maciej,Kubiński, Konrad,Misiak, Majus,Sk?adanowski, Andrzej,Demkowicz, Sebastian
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- Modified Amino Acid-Derived Phosphine-Imine Ligands for Palladium-Catalyzed Asymmetric Arylation of Cyclic N-Sulfonyl Imines
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A series of chiral phosphine-imine ligands were synthesized starting with α-amino acids and examined for palladium-catalyzed asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines. High catalytic activities (up to 99% yield) and high enantioselectivities (up to 98% ee) were achieved for cyclic N-sulfonyl aldimines and ketimines with five and six-membered ring structures. (Figure presented.).
- Zhou, Bo,Li, Kaizhi,Jiang, Chunhui,Lu, Yixin,Hayashi, Tamio
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supporting information
p. 1969 - 1975
(2017/06/09)
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- NOVEL COMPOUND, ORGANIC CATION TRANSPORTER 3 DETECTION AGENT, AND ORGANIC CATION TRANSPORTER 3 ACTIVITY INHIBITOR
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[Problem] The present invention addresses the problem of providing a novel compound. The present invention also addresses the problem of providing an OCT3 detection agent or an OCT3 activity inhibitor, which comprises the novel compound. [Solution] A compound represented by formula (A), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. ????????R1-R2-R3-R4?????(A)
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Paragraph 0686-0687; 0690
(2016/08/17)
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- Pushing the limits of catalytic C-H amination in polyoxygenated cyclobutanes
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A synthetic route to a new class of conformationally constrained iminosugars based on a 5-azaspiro[3.4]octane skeleton has been developed by way of Rh(ii)-catalyzed C(sp3)-H amination. The pivotal stereocontrolled formation of the quaternary C-N bond by insertion into the C-H bonds of the cyclobutane ring was explored with a series of polyoxygenated substrates. In addition to anticipated regioselective issues induced by the high density of activated α-ethereal C-H bonds, this systematic study showed that cyclobutane C-H bonds were, in general, poorly reactive towards catalytic C-H amination. This was demonstrated inter alia by the unexpected formation of a oxathiazonane derivative, which constitutes a very rare example of the formation of a 9-membered ring by way of catalyzed C(sp3)-H amination. A complete stereocontrol could be however achieved by activating the key insertion position as an allylic C-H bond in combination with reducing the electron density at the undesired C-H insertion sites by using electron-withdrawing protecting groups. Preliminary biological evaluations of the synthesized spiro-iminosugars were performed, which led to the identification of a new class of correctors of the defective F508del-CFTR gating involved in cystic fibrosis.
- Nocquet, Pierre-Antoine,Hensienne, Rapha?l,Wencel-Delord, Joanna,Laigre, Eugénie,Sidelarbi, Khadidja,Becq, Frédéric,Norez, Caroline,Hazelard, Damien,Compain, Philippe
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p. 2780 - 2796
(2016/03/05)
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- Modulators of HSP70/DnaK function and methods of use thereof
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Compositions and methods for modulating HSP70 function, particularly for the targeted killing of cancer cells, are disclosed.
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Page/Page column 40; 41
(2016/04/26)
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- Synthesis and Biological Evaluation of Fluorinated 3-Phenylcoumarin-7-O-Sulfamate Derivatives as Steroid Sulfatase Inhibitors
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In the present work, we report the initial results of our study on a series of 3-phenylcoumarin sulfamate-based compounds containing C-F bonds as novel inhibitors of steroid sulfatase. The new compounds are potent steroid sulfatase inhibitors, possessing more than 10 times higher inhibitory potency than coumarin-7-O-sulfamate. In the course of our investigation, compounds 2b and 2c demonstrated the highest inhibitory effect on the enzymatic steroid sulfatase assay; both had IC50 values of 0.27 μm (the IC50 value of coumarin-7-O-sulfamate is 3.5 μm, used as a reference).
- Demkowicz, Sebastian,Dako, Mateusz,Kozak, Witold,Krawczyk, Katarzyna,Witt, Dariusz,Maslyk, Maciej,Kubiski, Konrad,Rachon, Janusz
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p. 233 - 238
(2016/02/14)
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- Synthesis and steroid sulfatase inhibitory activities of: N -phosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates
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In the present work, we report convenient methods for the synthesis and biological evaluation of N-phosphorylated derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as potential steroid sulfatase (STS) inhibitors. Their binding modes were modeled using docking techniques. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta. All of the newly synthesised coumarin derivatives were powerful inhibitors of STS with IC50 values ranging between 0.19 and 0.78 μM. In particular, we found that 3-[4-(diphenoxy-phosphorylamino)-phenyl]-coumarin-7-O-sulfamate 10e and 3-[4-(dibenzyloxy-phosphorylamino)-phenyl]-coumarin-7-O-sulfamate 10f produced the highest inhibitory effects, with IC50 values of 0.19 and 0.24 μM, respectively (IC50 values of 1.38 μM for coumarin-7-O-sulfamate 2 and 1.03 μM for coumate 3 used as reference). The structure-activity relationships of the synthesized coumarin derivatives toward the STS enzyme were discussed.
- Da?ko, Mateusz,Mas?yk, Maciej,Kubiński, Konrad,Aszyk, Justyna,Rachon, Janusz,Demkowicz, Sebastian
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supporting information
p. 1146 - 1150
(2016/07/06)
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- Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1
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Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.
- Shah, Rachit,Strom, Alexander,Zhou, Andrew,Maize, Kimberly M.,Finzel, Barry C.,Wagner, Carston R.
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supporting information
p. 780 - 784
(2016/08/24)
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- NEW SUBSTITUTED BIPHENYL ANALOGUES AS DUAL INHIBITORS OF AROMATASE AND SULFATASE
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Provided are new biphenyl derivatives of formula (Ia). These compounds act as aromatase and sulfatase inhibitors. They are particularly useful for treating pathological conditions or diseases in which aromatase and sulfatase are involved. Moreover, provided are processes for the preparation of these compounds and pharmaceutical compositions containing said products and their use for the preparation of a medicament, in particular for the treatment of diseases characterized by aromatase and sulfatase activity such as hormone-dependent cancers.
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Page/Page column 30; 31
(2015/07/16)
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- BIARYL KINASE INHIBITORS
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The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
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Page/Page column 65; 66
(2015/11/02)
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- SUBSTITUTED IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TrkA) INHIBITORS
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The present application relates to a series of substituted imidazo[1,2-a]pyridine compounds of formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.
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Paragraph 0645; 0646
(2016/01/15)
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- DUAL ACTION CARBONIC ANHYDRASE INHIBITORS
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The present invention is directed to novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety substituted with a heterocycle or phosphinate and having sulfonamide, sulfamate or sulfamide groups. The present invention is also related to the use of these novel carbonic anhydrase IX inhibitors in cancer treatment, especially radiotherapy and chemotherapy and the use in treatment of infections.
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Page/Page column 76
(2015/03/13)
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- Regioselective sulfamoylation at low temperature enables concise syntheses of putative small molecule inhibitors of sulfatases
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Regioselective sulfamoylation of primary hydroxyl groups enabled a 5-step synthesis (overall yield 17%) of the first reported small molecule inhibitor of sulfatase-1 and 2, ((2S,3R,4R,5S,6R)-4,5-dihydroxy-2-methoxy-6-((sulfamoyloxy)methyl)tetrahydro-2H-pyran-3-yl)sulfamic acid, which obviated the use of hydroxyl protecting groups and is a marked improvement on the reported 9-step synthesis (overall yield 9%) employing hazardous trifluoromethylsulfonyl azide. The sulfamoylation methodology was used to prepare a range of derivatives of 1, and inhibition data was generated for Sulf-2, ARSA and ARSB.
- Miller, Duncan C.,Carbain, Benoit,Beale, Gary S.,Alhasan, Sari F.,Reeves, Helen L.,Baisch, Ulrich,Newell, David R.,Golding, Bernard T.,Griffin, Roger J.
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supporting information
p. 5279 - 5284
(2015/05/13)
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