- Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX
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Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1–4 carbon atoms; n = 1–4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.
- Das, Viswanath,El Anwar, Suzan,Holub, Josef,Kugler, Michael,Nekvinda, Jan,?ezá?ová, Pavlína,?ícha, Václav,Brynda, Ji?í,D?ubák, Petr,Dvo?anová, Jana,Fábry, Milan,Grüner, Bohumír,Gurská, Soňa,Hajdúch, Marián,Havránek, Miroslav,Král, Vlastimil,Li?ková, Barbora,Matějková, Stanislava,Medvedíková, Martina,Pospí?ilová, Klára
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- Synthesis and antiviral evaluation of nucleoside analogues bearing one pyrimidine moiety and two d-ribofuranosyl residues
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A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-D-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 μM, 24.3 μM, and 29.2 μM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-D-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-D-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-D-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 μM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.
- Andreeva, Olga V.,Belenok, Mayya G.,Garifullin, Bulat F.,Kataev, Vladimir E.,Lyubina, Anna P.,Man’kova, Maria A.,Saifina, Liliya F.,Semenov, Vyacheslav E.,Shulaeva, Marina M.,Slita, Alexander V.,Volobueva, Alexandrina S.,Voloshina, Alexandra D.,Yesaulkova, Iana L.,Zarubaev, Vladimir V.
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supporting information
(2021/07/06)
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- Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling
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Alzheimer's disease (AD) is the most common form of dementia, and up to now, there are no disease-modifying drugs available. Natural product hybrids based on the flavonoid taxifolin and phenolic acids have shown a promising pleiotropic neuroprotective profile in cell culture assays and even disease-modifying effects in vivo. However, the detailed mechanisms of action remain unclear. To elucidate the distinct intracellular targets of 7-O-esters of taxifolin, we present in this work the development and application of a chemical probe, 7-O-cinnamoyltaxifolin-alkyne, for target identification using activity-based protein profiling. 7-O-Cinnamoyltaxifolin-alkyne remained neuroprotective in all cell culture assays. Western blot analysis showed a comparable influence on the same intracellular pathways as that of the lead compound 7-O-cinnamoyltaxifolin, thereby confirming its suitability as a probe for target identification experiments. Affinity pulldown and MS analysis revealed adenine nucleotide translocase 1 (ANT-1) and sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) as intracellular interaction partners of 7-O-cinnamoyltaxifolin-alkyne and thus of 7-O-esters of taxifolin.
- Gunesch, Sandra,Soriano-Castell, David,Lamer, Stephanie,Schlosser, Andreas,Maher, Pamela,Decker, Michael
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p. 3823 - 3837
(2020/11/16)
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- Protecting-Group-Free Total Synthesis of Chatenaytrienin-2
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An efficient seven-step, protecting-group-free first total synthesis of chatenaytrienin-2 based on ring-closing metathesis and C(sp)-C(sp3) Sonogashira coupling with a 36.5% overall yield has been described. The ready availability of starting m
- Kunkalkar, Rupesh A.,Fernandes, Rodney A.
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p. 12216 - 12220
(2019/10/11)
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- Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil, 3,6-dimethyluracil, thymine, and quinazoline-2,4-dione moieties
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A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with protected azido β-D-ribofuranose. The obtained compounds differ in both the nature of the pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the β-D-ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were evaluated for their cytotoxicity in vitro.
- Andreeva, Olga V.,Belenok, Maya G.,Saifina, Liliya F.,Shulaeva, Marina M.,Dobrynin, Alexey B.,Sharipova, Radmila R.,Voloshina, Alexandra D.,Saifina, Alina F.,Gubaidullin, Aidar T.,Khairutdinov, Bulat I.,Zuev, Yuriy F.,Semenov, Vyacheslav E.,Kataev, Vladimir E.
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supporting information
(2019/11/05)
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- Photoinduced, Copper-Promoted Regio- and Stereoselective Decarboxylative Alkylation of α,β-Unsaturated Acids with Alkyl Iodides
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The first example of UV light-induced, copper-catalyzed regio- and stereoselective decarboxylative coupling of α,β-unsaturated acids with alkyl iodides was reported. Under standard conditions, the 1°, 2°, and 3° alkyl iodides proceeded smoothly with the E-selective alkenes obtained in uniformly good yields and high stereoselectivities.
- Wang, Chao,Lei, Yingjie,Guo, Mengzhun,Shang, Qinyu,Liu, Hong,Xu, Zhaoqing,Wang, Rui
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supporting information
p. 6412 - 6415
(2017/12/08)
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- Lewis Acid-Catalyzed Intramolecular [3+2] Cross-Cycloaddition of Aziridine 2,2-Diesters with Conjugated Dienes for Construction of Aza-[n.2.1] Skeletons
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A novel Lewis acid-catalyzed [3+2] intramolecular cross-cycloaddition (IMCC) between aziridine 2,2-diesters and conjugated dienes has been developed. This is the first regiospecific IMCC of intramolecular 1,3-dipolar cycloadditions of azomethine ylides with carbon=carbon double bonds, and supplies a general and efficient strategy for construction of structurally complex and diverse aza-[n.2.1] skeletons. The [3+2]IMCC could be carried out under mild conditions and in gram scale. More importantly, 3-alkyl-substituted aziridines were also successful. The excellent structural diversity, the facile operation and the versatile post-modifications will support the applications of the [3+2]IMCC in natural products synthesis and drugs discovery.
- Zhan, Yizhou,Liu, Tao,Ren, Jun,Wang, Zhongwen
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supporting information
p. 17862 - 17866
(2017/11/27)
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- Reversible Stereoselective Folding/Unfolding Fueled by the Interplay of Photoisomerism and Hydrogen Bonding
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A linear molecular architecture equipped with complementary three-fold hydrogen-bonding units embedded with a photoswitchable trans-tetrafluoroazobenzene moiety was synthesized. The transto cis photoisomerism of the azobenzene unit induced drastic changes
- Opie, Christopher R.,Kumagai, Naoya,Shibasaki, Masakatsu
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supporting information
p. 3349 - 3353
(2017/03/17)
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- Approaches to polyunsaturated sphingolipids: New conformationally restrained analogs with minimal structural modifications
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Conformationally restrained sphingolipids 1-4, arising from the introduction of a polyene or a polyenyne moiety as part of the sphingoid backbone, have been synthesized. While addition of polyene acetylides 6 and 7 to Garner's aldehyde afforded the corres
- Nieves, Ingrid,Abad, Jos-Luis,Montes, L. Ruth,Goi, Flix M.,Delgado, Antonio
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p. 605 - 612
(2016/01/15)
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- Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero-Functionalized Triazoles
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The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.
- Wang, Weiguo,Peng, Xianglong,Wei, Fang,Tung, Chen-Ho,Xu, Zhenghu
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supporting information
p. 649 - 653
(2016/02/27)
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- Synthesis of Non-natural, Frame-Shifted Isoprenoid Diphosphate Analogues
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A set of synthetic approaches was developed and applied to the synthesis of eight frame-shifted isoprenoid diphosphate analogues. These analogues were designed to increase or decrease the methylene units between the double bonds and/or the pyrophosphate m
- Temple, Kayla J.,Wright, Elia N.,Fierke, Carol A.,Gibbs, Richard A.
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supporting information
p. 6038 - 6041
(2016/12/09)
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- Gold(I)-Catalysed Cyclisation of Alkynoic Acids: Towards an Efficient and Eco-Friendly Synthesis of γ-, δ- and ?-Lactones
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The improved synthesis of γ-, δ- and ?-lactones using a dinuclear N-heterocyclic carbene (NHC)-gold(I) catalyst is reported. This solvent-free process provides access to γ- and δ-lactones in high regio- and stereoselectivity. Reactions were performed at l
- Gasperini, Danila,Maggi, Lorenzo,Dupuy, Stéphanie,Veenboer, Richard M. P.,Cordes, David B.,Slawin, Alexandra M. Z.,Nolan, Steven P.
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supporting information
p. 3857 - 3862
(2016/12/16)
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- TRIAZOLE MACROCYCLE SYSTEMS
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The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production.
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Paragraph 0275
(2016/02/22)
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- Synthesis of a bistable [3]rotaxane and its pH-controlled intramolecular charge-transfer behavior
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A [3]rotaxane 1 involving two naphtho-21-crown-7 (N21C7) rings and a dumbbell-shaped component 4 was synthesized. The dumbbell-shape molecule 4 contains one viologen nucleus, two secondary alkyl ammonium sites and two phenyl stoppers. After threading the N21C7 ring with the thread-like ammonium guest 3, the copper(I)-catalyzed Huisgen alkyne-azide 1,3-dipolar cycloaddition (CuAAC "click" reaction), was performed to connect the pseudorotaxanes with viologen unit 2 and generate 1. Through treating the [3]rotaxane by the base and acid circularly, the two N21C7 rings can make shuttling motion along the axle. Meanwhile the distance between the electron-deficient viologen unit and the electron-rich naphthol group can be adjusted precisely along with a remarkable intramolecular charge-transfer (CT) behavior.
- Wang, Hui,Zhang, Zhi-Jun,Zhang, Heng-Yi,Liu, Yu
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supporting information
p. 563 - 567
(2013/07/27)
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- Synthesis of frame-shifted farnesyl diphosphate analogs
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A set of synthetic approaches were developed and applied to the synthesis of eight frame-shifted farnesyl diphosphate (FPP) analogs. These analogs bear increased or decreased methylene units between the double bonds and/or diphosphate moieties of the isop
- Placzek, Andrew T.,Hougland, James L.,Gibbs, Richard A.
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supporting information; experimental part
p. 4038 - 4041
(2012/10/07)
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- Atom-economical synthesis of functionalized cycloalkanes via catalytic redox cycloisomerization of propargyl alcohols
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An atom-economical procedure for the direct synthesis of cycloalkanes from propargyl alcohols is reported. This high-yielding one-pot process involves a sequence consisting of a Ru-catalyzed redox isomerization of ynols into enones or an enal followed by
- Trost, Barry M.,Breder, Alexander,Kai, Bao
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supporting information; experimental part
p. 1708 - 1711
(2012/06/18)
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- One-pot catalytic enantioselective synthesis of tetrahydropyridines via a nitro-mannich/hydroamination cascade
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The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This approach utilizes an asymmetric organocatalytic nitro-Mannich reaction followed by a gold-catalyzed alkyne hydroamination/ isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities.
- Barber, David M.,Sanganee, Hitesh J.,Dixon, Darren J.
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supporting information
p. 5290 - 5293
(2013/01/15)
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- Clickable long-wave "mega-stokes" fluorophores for orthogonal chemoselective labeling of cells
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Dyes that can easily be tied: The synthesis of water-soluble far-red/NIR emitting polymethine-based dyes with clickable functionalities (azide, alkyne) and their application in cell-surface labeling are presented.
- Nagy, Krisztina,Orban, Erika,Bosze, Szilvia,Kele, Peter
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experimental part
p. 773 - 777
(2010/07/07)
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- Design, synthesis, and BK channel-opening activity of hexahydrodibenzazepinone derivatives
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In order to explore new scaffolds for large-conductance Ca2+-activated K+ channel (BK channel) openers, we carried out molecular design and synthesis on the basis of the following two concepts: (1) introduction of a heteroatom into t
- Tashima, Toshihiko,Toriumi, Yoshimi,Mochizuki, Yumi,Nonomura, Taro,Nagaoka, Satoru,Furukawa, Katsuo,Tsuru, Hiromichi,Adachi-Akahane, Satomi,Ohwada, Tomohiko
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p. 8014 - 8031
(2007/10/03)
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- ALKYNYL PYRROLOPYRIMIDINES AND RELATED ANALOGS AS HSP90-INHIBITORS
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Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders. Methods of synthesis and use of such compounds are also described and claimed.
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Page/Page column 93
(2010/11/24)
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- 7alpha- and 17alpha-substituted estrogens containing tridentate tricarbonyl rhenium/technetium complexes: synthesis of estrogen receptor imaging agents and evaluation using microPET with technetium-94m.
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To develop technetium and rhenium-labeled imaging agents for estrogen receptor (ER) positive breast tumors, we have prepared tridentate metal tricarbonyl chelates substituted at the 7alpha- and 17alpha-positions of estradiol. Some of the Re(CO)(3) conjuga
- Luyt, Leonard G,Bigott, Heather M,Welch, Michael J,Katzenellenbogen, John A
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p. 4977 - 4989
(2007/10/03)
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- Regioselective monoalkylation of calixarenes. Synthesis of homodimer calixarenes
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The selective monoalkylation at the smaller (lower) rim of the p-tert- butylcalix[4]- and -[6]arenes using bis(butyltin)oxide and different alkylating agents is described. The procedure is remarkable for the mild conditions used allowing an efficiently access to monoalkylated calixarene derivatives in moderate to good yields. Monoalkynylcalix[4]arene and monoalkynylcalix[6]arene have been synthetically exploited for the synthesis of bis-calix[n]arenes (n = 4, 6) with a diyne bridge by oxidative coupling of alkynes. In addition, intermolecular methathesis of the obtained monoalkenylcalix[4]arene allowed the preparation of bis-calix[4]arene that are single bridged at the smaller (lower) rim with a 2-butenyl moiety.
- Santoyo-Gonzalez, Francisco,Torres-Pinedo, Antonio,Sanchez-Ortega, Adolfo
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p. 4409 - 4414
(2007/10/03)
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- A Stille cyclisation approach to (-)-periplanone-B: Studies in alkene-selective ring-closing metathesis and an improved chromium(II)-mediated synthesis of (E)-alkenylstannanes from aldehydes
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A synthesis of the dienone 7 via an efficient intramolecular Stille cross-coupling reaction, an improved chromium(II)-mediated synthesis of (E)-alkenylstannanes from aldehydes using Bu3SnCHI2 in DMF, and a synthesis of the substituted (-)-dienone 25 via ring-closing alkene metathesis to give dihydropyran 22 are described. The synthesis of (-)-dienone 25 constitutes a formal synthesis of (-)-periplanone-B. The Royal Society of Chemistry 1999.
- Hodgson, David M.,Foley, Anne M.,Boulton, Lee T.,Lovell, Peter J.,Maw, Graham N.
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p. 2911 - 2922
(2007/10/03)
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- Competition among 1,2- and 1,3-Acyl Shifts, and Reduction Reactions, in the UV Irradiation of Cyclopent-2-enones bearing a C-3 Terminal-alkyne Chain
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UV irradiation in MeCN of 3-(pent-4'-ynyl)cyclopent-2-enone 13 (prepared from 3-iodocyclopent-2-enone 12 and the cuprate obtained from 5-iodopent-1-yne 10a) gave mainly hydrogen-addition product of the primary photocycloadduct 15, tricyclo3,7>decan-4-one 18a (56percent), besides minor 16 (22percent), 19 (12percent), 17 (8percent) and traces of 15 (2percent).In acetone as solvent, formation of 18a remained the main route owing, presumably, to strain release on hydrogen addition in the primary photocycloadduct 15.In CD3CN as solvent, photoconversion of 13 was slower, deuterium was incorporated at the tertiary bridgheads in the reduction product 18b, and the product balance was slightly in favour of the 1,2-acyl-shift product 16.This situation was not substantially ameliorated even in the typically reduction-hindering solvent hexadeuterioacetone.UV irradiation of the side-chain homologous 3-(hex-5'-ynyl)cyclopent-2-enone 14 in MeCN led to mainly the products of photocycloaddition (tricyclo3,7>undec-10-en-7-one 20) and 1,3-acyl-shift (tricyclo1,6>undec-10-en-7-one 21), albeit in modest yields, 12 and 24percent, respectively.
- Mancini, Ines,Cavazza, Marino,Guella, Graziano,Pietra, Francesco
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p. 2181 - 2186
(2007/10/02)
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- Formation of seven- and eight-membered rings by Mn(III)-based oxidative free-radical cyclization
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Oxidative free-radical cyclizations of acetoacetates 1, 8, 17, and 20 with Mn(OAc)3·2H2 and Cu(OAc)2·H2O in acetic acid provide cycloheptenes and cyclooctenes in moderate to good yield. Tandem cyclizations of 28, 35 and 51 provide bicyclo[4.2.1]nonanes, bicyclo[5.2.1]decanes, bicyclo[5.3.0]decanes and bicyclo[6.3.0]undecanes.
- Snider, Barry B.,Merritt, John E.
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p. 8663 - 8678
(2007/10/02)
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- Strong-Base-Induced Intramolecular Cycloaddition of Homophthalic Anhydrides: An Efficient Synthesis of Polycyclic peri-Hydroxy Aromatic Compounds
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A strong-base-induced intramolecular cycloaddition reaction of homophthalic anhydrides has been examined as a method for preparing nonlinear polycyclic peri-hydroxy aromatic compounds.
- Kita, Yasuyuki,Okunaka, Ryuichi,Honda, Takao,Shindo, Miki,Taniguchi, Miyako,et al.
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p. 119 - 125
(2007/10/02)
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- Preparation and Diels-Alder Reactivity of Thieneo- and Thienopyran-3-ones, Stable 2,3-Dimethylenethiophene Derivatives; Synthesis of Benzothiophenes
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The thienopyran-3-ones (7) and the isomeric pyranones, e.g. (26) are stable derivatives of 2,3-dimethylenethiophene (3).When heated with alkynes they undergo Diels-Alder reaction to give, after loss of carbon dioxide, benzothiophenes.With un
- Jackson, P. Mark,Moody, Christopher J.,Shah, Pritom
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p. 2909 - 2918
(2007/10/02)
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- Cyclisation de composes acetyliniques carbonyles via leur ether d'enol silyle: II. Synthese et reactivite de quelques ethers d'enols derivees d'aldehydes ou de cetones acetyleniques terminaux
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A number of silyl enol ethers of ω-acetylenic ketones or aldehydes have been prepared following various literature procedures which are compared to each other.By treatment with mercury (II) chloride (1.1 equiv.) in the presence of HMDS (0.2 or 1.5 equiv.) at room temperature, followed by acidification with aqueous HCl-NaI, silyl enol ethers 1, 2, 3, 9, 11, 12 and 13 are cyclized in high yield into 2-alkylidene-1-oxocyclopentanes, methylene- spiro or poly-cyclanones, a methylene cyclopentane unit being formed in the reaction.In the same way, from silyl enol ethers 4, 8 and 10 a methylenecyclohexane unit is formed.In all the products the exocyclic position of the C=C double bond so formed is fully maintained.
- Boaventura, Maria-Amelia,Drouin, Jacques
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p. 1015 - 1026
(2007/10/02)
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- New Myocardial Imaging Agents: Stabilization of Radioiodine as a Terminal Vinyl Iodide Moiety on Tellurium Fatty Acids
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To determine the myocardial uptake and retention properties of radioiodinated tellurium fatty acids, we prepared two new tellurium fatty acids in which iodine-125 has been chemically stabilized by attachment as a trans-vinyl iodide (I-CH=CH-R-Te-R'-COOH)
- Knapp, F. F.,Goodman, M. M.,Callahan, A. P.,Ferren, L. A.,Kabalka, G. W.,Sastry, K. A. R.
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p. 1293 - 1300
(2007/10/02)
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