- A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants
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FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4π-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.
- Chen, Yong,Coussanes, Guilhem,Souris, Caroline,Aillard, Paul,Kaldre, Dainis,Runggatscher, Kathrin,Kubicek, Stefan,Di Mauro, Giovanni,Maryasin, Boris,Maulide, Nuno
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Read Online
- 68Ga/DOTA- and 64Cu/NOTA-phthalocyanine conjugates as fluorescent/PET bimodal imaging probes
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In this paper, we describe the synthesis and characterization of a series of new bimodal probes combining water-soluble sulfonated zinc phthalocyanine (ZnPc) as a fluorescence imaging unit and either 68Ga/1,4,7,10- tetraazocyclododecane-N,N′N″,N′″-tetraacetic acid (DOTA) or 64Cu/1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for PET imaging. The two moieties were linked through aliphatic chains of different lengths to modulate amphiphilicity. Labeling of DOTA- or NOTA-ZnPc conjugates with 68Ga (t1/2 = 68 min) and 64Cu (t 1/2 = 12.7 h) was performed at 100 C for 15 min with >90% efficiency for all conjugates. In vitro plasma stability assays demonstrated high stability of the 64Cu/NOTA-ZnPc conjugate, which remained intact over a 24 h time period, and reasonably high stability of the 68Ga/DOTA-ZnPc conjugate, which released up to 7% of free 68Ga over a 3 h period. Based on in vitro plasma stability results, we performed biodistribution studies on two 64Cu-labeled derivatives, which allowed us to select a single candidate for preliminary in vivo experiments. Fluorescence and PET imaging confirmed the potential of these novel conjugates to act as bimodal probes.
- Ranyuk, Elena,Lebel, Réjean,Bérubé-Lauzière, Yves,Klarskov, Klaus,Lecomte, Roger,Van Lier, Johan E.,Guérin, Brigitte
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Read Online
- HYDROXY-PYRIDINALDOXIME SCAFFOLDS
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The present invention relates to a compound of formula (I). It also relates to a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable support. Finally, it relates to the use of such a compound as a medicine, preferably in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent; in the treatment of neurological diseases such as Alzheimer's disease; and/or in the treatment of cancer.
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- Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin**
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Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1, using a rhodium-catalyzed distal selective allene-ynamide Pauson–Khand reaction. A regio- and enantioselective epoxidation under chiral phase-transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium-catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N-acetylcysteamine, was studied and revealed unanticipated transformations, including bis-thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.
- W?rmer, Gustav J.,Villadsen, Nikolaj L.,N?rby, Peter,Poulsen, Thomas B.
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supporting information
p. 10521 - 10525
(2021/03/29)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001987-001989
(2020/06/19)
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- Design, synthesis and structure-activity relationships of novel 15-membered macrolides: Quinolone/quinoline-containing sidechains tethered to the C-6 position of azithromycin acylides
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In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.
- Aldrich, Courtney,Brody, Scott,Cushman, Mark,Fan, Bing-Zhi,Hiasa, Hiroshi,Liang, Jian-Hua,Lv, Wei,Yang, Zhao-Yong
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 4253; 4254
(2019/07/10)
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- A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants
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FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4?€-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.
- Chen, Yong,Coussanes, Guilhem,Souris, Caroline,Aillard, Paul,Kaldre, Dainis,Runggatscher, Kathrin,Kubicek, Stefan,Di Mauro, Giovanni,Maryasin, Boris,Maulide, Nuno
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supporting information
p. 13772 - 13777
(2019/09/30)
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- Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds
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Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure–activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4-substitution on the triazole ring and use of an unbranched, one-carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.
- Guan, Jinming,Tjhin, Erick T.,Howieson, Vanessa M.,Kittikool, Tanakorn,Spry, Christina,Saliba, Kevin J.,Auclair, Karine
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supporting information
p. 2677 - 2683
(2018/12/11)
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- Design of Gut-Restricted Thiazolidine Agonists of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5)
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Bile acid signaling and metabolism in the gastrointestinal tract have wide-ranging influences on systemic disease. G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors in bile acid sensing, with demonstrated influence on metabolic, inflammatory, and proliferative processes. The pharmacologic utility of TGR5 agonists has been limited by systemic target-related effects such as excessive gallbladder filling and blockade of gallbladder emptying. Gut-restricted TGR5 agonists, however, have the potential to avoid these side effects and consequently be developed into drugs with acceptable safety profiles. We describe the discovery and optimization of a series of gut-restricted TGR5 agonists that elicit a potent response in mice, with minimal gallbladder-related effects. The series includes 12 (TGR5 EC50: human, 143 nM; mouse, 1.2 nM), a compound with minimal systemic availability that may have therapeutic value to patients with type 2 diabetes mellitus, nonalcoholic steatohepatitis, or inflammatory bowel disease.
- Chen, Tao,Reich, Nicholas William,Bell, Noah,Finn, Patricia D.,Rodriguez, David,Kohler, Jill,Kozuka, Kenji,He, Limin,Spencer, Andrew G.,Charmot, Dominique,Navre, Marc,Carreras, Christopher W.,Koo-Mccoy, Samantha,Tabora, Jocelyn,Caldwell, Jeremy S.,Jacobs, Jeffrey W.,Lewis, Jason Gustaf
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supporting information
p. 7589 - 7613
(2018/09/12)
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- Compound design guidelines for evading the efflux and permeation barriers of Escherichia coli with the oxazolidinone class of antibacterials: Test case for a general approach to improving whole cell Gram-negative activity
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Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (7.4 1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.
- Spaulding, Andrew,Takrouri, Khuloud,Mahalingam, Pornachandran,Cleary, Dillon C.,Cooper, Harold D.,Zucchi, Paola,Tear, Westley,Koleva, Bilyana,Beuning, Penny J.,Hirsch, Elizabeth B.,Aggen, James B.
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supporting information
p. 5310 - 5321
(2017/11/13)
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- Modular, Concise, and Efficient Synthesis of Highly Functionalized 5-Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence
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An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.
- Tran, Ga?l,Gomez Pardo, Domingo,Tsuchiya, Tomoki,Hillebrand, Stefan,Vors, Jean-Pierre,Cossy, Janine
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supporting information
p. 3414 - 3417
(2015/07/28)
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- Autotaxin inhibitors
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The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.
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Page/Page column
(2014/06/25)
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- Radical [3 + 2]-annulation of divinylcyclopropanes: Rapid synthesis of complex meloscine analogs
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A radical [3 + 2]-divinylcyclopropane annulation cascade has been extended to encompass five D-ring variants of the meloscine/epimeloscine core structure. Representative ABCD tetracyclic intermediates were further elaborated with novel substituted E-rings through subsequent transformations of advanced intermediates that provided opportunities for late-stage variation of the B-ring (lactam) N-substituents which were also developed.
- Zhang, Hanmo,Jeon, Kyu Ok,Hay, E. Ben,Geib, Steven J.,Curran, Dennis P.,Laporte, Matthew G.
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supporting information
p. 94 - 97
(2014/01/23)
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- Catalytic coupling of arene C-H bonds and alkynes for the synthesis of coumarins: Substrate scope and application to the development of neuroimaging agents
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C-H bond functionalization offers strategically novel approaches to complex organic compounds. However, many C-H functionalization reactions suffer from poor compatibility with Lewis basic functional groups, especially amines, which are often essential for biological activity. This study describes a systematic examination of the substrate scope of catalytic hydroarylation in the context of complex amino coumarin synthesis. The choice of substrates was guided by the design and development of the next generation of fluorescent false neurotransmitters (FFNs), neuroimaging probes we recently introduced for optical imaging of neurotransmission in the brain. Comparison of two mild protocols using catalytic PtCl4 or Au (PPh3)Cl/AgSbF6 revealed that each method has a broad and mutually complementary substrate scope. The relatively less active platinum system out-performed the gold catalyst with indole substrates lacking substitution at the C-3 position and provided higher regioselectivity in the case of carbazole-based substrates. On the other hand, the more active gold catalyst demonstrated excellent functional group tolerance, and the ability to catalyze the formation of strained, helical products. The development of these two protocols offers enhanced substrate scope and provides versatile synthetic tools required for the structure-activity examination of FFN neuroimaging probes as well as for the synthesis of complex coumarins in general.
- Vadola, Paul A.,Sames, Dalibor
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p. 7804 - 7814,11
(2020/10/15)
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- ANTICANCER DERIVIATIVES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
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The invention relates to nicotinamide derivatives which can be used as anticancer drugs.
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Page/Page column 14
(2012/04/23)
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- Stereoselective spirolactam synthesis via palladium catalyzed arylative allene carbocyclization cascades
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A diastereoselective arylative carbocyclization of pro-nucleophile-linked allenes with aryl and heteroaryl halides to provide spirocyclic lactam products with moderate to high diastereoselectivities and good yields under Pd(0) catalysis is reported. Being operationally simple and tolerant of multiple points of diversity, this complexity building reaction cascade, in which two new carbon-carbon bonds and one new heterocyclic ring are created, should be of high value in both complex natural product synthesis as well as compound library synthesis.
- Li, Meiling,Dixon, Darren J.
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supporting information; experimental part
p. 3784 - 3787
(2010/11/04)
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- 6-SUBSTITUTED 2,3,4,5-TETRAHYDRO-1H-BENZO[d]AZEPINES AS 5-HT2C RECEPTOR AGONISTS
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The present invention provides 6-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines of Formula (I) as selective 5-HT2C receptor agonists for the treatment of 5-HT2C associated disorders including obesity, obsessive/compulsive disorde
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Page/Page column 49
(2008/06/13)
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- Prodrugs activated by targeted catalytic proteins
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Prodrugs that are activated by and conjugated to a catalytic antibody conjugated to a moiety that binds to a tumor cell population are provided.
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- Synthesis and structure-antibacterial activity relationships of 7-(3- amino-1-propynyl and 3-amino-1-propenyl)quinolones
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7-(3-Amino-1-propynyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (7a) and some related compounds (7b-f, 8a, b, 9) were prepared via palladium(0)-catalyzed cross-coupling reaction of 7- iodoquinolone 12 with acetylenic compounds and their antibacterial activity was tested. The methylene homologue (7d) and the N-methyl derivative (7e) of 7a showed essentially the same activity as that of 7a. Addition of methyl group(s) to C'-3 of 7a (giving 7b, c) reduced the activity. The hydrogenation of 7a to (Z)-3-amino-1-propenyl (8a), (E)-3-amino-1-propenyl (8b) and 3- amino-1-propyl (9) compounds retained or enhanced the activity of 7a. Among the compounds prepared, 8a was the most active, but was less active than ciprofloxacin (1). In order to get insight into structure-activity relationships, the spatial distribution of the amino groups of 7a, 8a, b, and 9 was examined by means of computer-aided molecular modeling.
- Fujita, Masahiro,Chiba, Katsumi,Nakano, Junji,Tominaga, Yukio,Matsumoto, Jun-Ichi
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p. 631 - 638
(2007/10/03)
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