- Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer
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As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to
- Hu, De-Xuan,Tang, Wen-Lin,Zhang, Yu,Yang, Hao,Wang, Wenjie,Agama, Keli,Pommier, Yves,An, Lin-Kun
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p. 7617 - 7629
(2021/06/25)
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- Modification of 5-methylphenanthridium from benzothiazoles to indoles as potent FtsZ inhibitors: Broadening the antibacterial spectrum toward vancomycin-resistant enterococci
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The death caused by pathogenic bacteria has always been a severe threat to mankind. The prevalence of drug resistance among bacteria underscores an urgent goal for new antibacterial agents with novel mode of action. Here we first designed and synthesized a class of benzothiazolyl-5-methylphenanthridium derivatives and evaluated their antibacterial activity. On this basis, we further designed and synthesized another class of novel indolyl-5-methylphenanthridium derivatives by optimizing the benzothiazolyl-5-methylphenanthridium core and evaluated their antibacterial activity targeting the bacterial cell division protein FtsZ. The results showed that the indolyl-5-methylphenanthridium derivatives had greatly improved activity against various drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE). Among them, compound C5 displayed excellent antibacterial activity against susceptible (MIC = 1 μg/mL), methicillin-resistant and clinical isolated S. aureus (MIC = 2 μg/mL). With low hemolytic activity towards mice red blood cells, C5 exhibited good antibacterial effect in vivo in preliminary pharmacodynamic assay. More importantly, C5 was difficult to induce bacterial resistance. Further mechanism studies proved that C5 could inhibit bacterial cell division by promoting FtsZ polymerization, leading to disorderly polymerization and disordered knots. Therefore, our findings suggest that this class of novel indolyl-5-methylphenanthridium derivatives are promising for future antibacterial agents.
- Chen, Weijin,Ma, Shutao,Song, Di,Zhang, Na,Zhang, Nan,Zhang, Panpan,Zhang, Shenyan
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- Stereoinvertive C–C Bond Formation at the Boron-Bound Stereogenic Centers through Copper-Bipyridine-Catalyzed Intramolecular Coupling of α-Aminobenzylboronic Esters
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Enantiospecific intramolecular Suzuki–Miyaura-type coupling with α-(2-halobenzoylamino)benzylboronic esters to give 3-substituted isoindolinones is achieved by using copper catalysts with 2,2′-bipyridine-based achiral ligands. Enantioenriched α-aminobenzylboron reactants bearing a hydrogen atom at the boron-bound stereogenic carbons undergo stereoinvertive coupling in the presence of a 6-phenyl-2,2′-bipyridine ligand with high enantiospecificity. α-Aminobenzylboronates bearing fully substituted boron-bound stereogenic centers also gave the 3,3-disubstituted isoindolinones with stereospecific stereochemical inversion in the presence of simple 2,2′-bipyridine as a ligand.
- Suginome, Michinori,Yamamoto, Takeshi,Yoshinaga, Yukako
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supporting information
p. 7251 - 7255
(2020/03/23)
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- GPR40 AGONISTS
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This disclosure is directed, at least in part, to GPR40 agonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR40 agonists are gut-restricted compounds. In some embodiments, the GPR40 agonists are full agonists or partial agonists. In some embodiments, the condition or disorder is a metabolic disorder, such as diabetes, obesity, nonalcoholic steatohepatitis (NASH), or a nutritional disorder such as short bowel syndrome.
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Paragraph 00243; 00244
(2020/12/11)
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- Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles
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Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.
- Chen, Li-Yuan,Chuang, Ta-Hsien,Lai, Chin-Hung,Tang, Rong-Shiow
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supporting information
p. 9337 - 9341
(2020/12/21)
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- C-H to C-N Cross-Coupling of Sulfonamides with Olefins
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Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp3)-N fragment coupling reaction between terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/SOX (sulfoxide-oxazoline) catalyzed intermolecular allylic C-H amination. A range of (56) allylic amines are furnished in good yields (avg. 75%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). Mechanistic studies reveal that the SOX ligand framework is effective at promoting functionalization by supporting cationic π-allyl Pd.
- Ma, Rulin,Christina White
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supporting information
p. 3202 - 3205
(2018/03/13)
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- Synthesis of Substituted Naphthalenes by 1,4-Palladium Migration Involved Annulation with Internal Alkynes
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The palladium catalyzed annulation of 1-bromo-2-vinylbenzene derivatives with internal alkynes was realized for the efficient synthesis of substituted naphthalenes. A controllable aryl to vinylic 1,4-palladium migration process is the key for success.
- Wei, Dong,Hu, Tian-Jiao,Feng, Chen-Guo,Lin, Guo-Qiang
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supporting information
p. 743 - 748
(2018/07/25)
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- Ni-Catalyzed Alkene Carboacylation via Amide C-N Bond Activation
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We report Ni-catalyzed formal carboacylation of o-allylbenzamides with arylboronic acid pinacol esters. The reaction is triggered by oxidative addition of an activated amide C-N bond to a Ni(0) catalyst and proceeds via alkene insertion into a Ni(II)-acyl bond. The exo-selective carboacylation reaction generates 2-benzyl-2,3-dihydro-1H-inden-1-ones in moderate to high yields (46-99%) from a variety of arylboronic acid pinacol esters and substituted o-allylbenzamides. These results show that amides are practical substrates for alkene carboacylation via amide C-N bond activation, and this approach bypasses challenges associated with alkene carboacylation triggered by C-C bond activation.
- Walker, James A.,Vickerman, Kevin L.,Humke, Jenna N.,Stanley, Levi M.
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supporting information
p. 10228 - 10231
(2017/08/10)
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- Palladium-catalyzed ring-opening of cyclopropyl benzamides: Synthesis of benzo[c]azepine-1-ones via C(sp3)-H functionalization
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A variety of difficult to obtain benzo[c]azepine-1-ones are synthesized via a novel palladium-catalyzed, silver-promoted intramolecular cyclization of cyclopropyl benzamides. This biologically important class of molecules is prepared in an efficient and high-yielding manner from easily accessible starting materials. Both aryl bromides and iodides are effective substrates for the transformation. Mechanistic studies indicate that the reaction proceeds through a cyclopropyl C(sp3)-H cleavage step, followed by ring-opening, deprotonation, and reductive elimination.
- Ladd, Carolyn L.,Roman, Daniela Sustac,Charette, André B.
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supporting information
p. 4479 - 4487
(2013/06/26)
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- Nickel or phenanthroline mediated intramolecular arylation of sp 3 C-H bonds using aryl halides
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The development of the intramolecular arylation of sp3 C-H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)2 or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates.
- Wertjes, William C.,Wolfe, Lydia C.,Waller, Peter J.,Kalyani, Dipannita
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supporting information
p. 5986 - 5989
(2014/01/06)
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- A general route for 13C-labeled fluorenols and phenanthrenols via palladium-catalyzed cross-coupling and one-carbon homologation
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A series of 13C-labeled polyaromatic hydrocarbons (PAHs), fluorenols and phenanthrenols were synthesized from commercially available 13C-labeled starting material giving rise to M + 6 isotopomers. This was accomplished using key pall
- Wu, Ruilian,Silks,Olivault-Shiflett, Morgane,Williams, Robert F.,Ortiz, Erick G.,Stotter, Philip,Kimball, David B.,Martinez, Rodolfo A.
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p. 581 - 586
(2013/11/06)
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- Antiestrogenic N-(4-hydroxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-hydroxybenzamides: Influence of hydrophobic groups substituted in the ortho-position of the benzamide-fragment on activity
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Experiments are reported here to develop compounds with antiestrogenic and mammary tumor inhibiting properties. Analogues with hydrophobic groups in 2- or 2,6-position of the benzamide-fragment of N-(4-hydroxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-hydroxy
- Hartmann,Vom Orde,Schonenberger
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