- Identification and optimization of biphenyl derivatives as novel tubulin inhibitors targeting colchicine-binding site overcoming multidrug resistance
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Microtubule targeting agents (MTAs) are among the most successful chemotherapeutic drugs, but their efficacy is often limited by the development of multidrug resistance (MDR). Therefore, the development of novel MTAs with the ability to overcome MDR is urgently needed. In this contribution, through modification of the unsymmetric biaryl compounds, we discovered a novel compound dxy-1-175 with potent anti-proliferative activity against cancer cells. Mechanistic study revealed that dxy-1-175 inhibited tubulin polymerization by interacting with the colchicine-binding site of tubulin, which caused cell cycle arrest at G2/M phase. Based on the predicted binding model of dxy-1-175 with tubulin, a series of new 4-benzoylbiphenyl analogues were designed and synthesized. Among them, the hydrochloride compound 12e with improved solubility and good stability in human liver microsome, exhibited the most potent anti-proliferative activity with IC50 value in the low nanomolar range, and markedly inhibited the growth of breast cancer 4T1 xenograft in vivo. Notably, 12e effectively overcame P-gp-mediated MDR and our preliminary data suggested that 12e may not be a substrate of P-glycoprotein (P-gp). Taken together, our study reveals a novel MTA 12e targeting the colchicine-binding site with potent anticancer activity and the ability to circumvent MDR.
- Cheng, Bao,Zhu, Guirong,Meng, Linghua,Wu, Guolin,Chen, Qin,Ma, Shengming
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supporting information
(2021/11/22)
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- A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects
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We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.
- Ghinato, Simone,Territo, Davide,Maranzana, Andrea,Capriati, Vito,Blangetti, Marco,Prandi, Cristina
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p. 2868 - 2874
(2021/01/21)
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- Mitochondrial targeting fluorescent probe as well as synthesis method and application thereof
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The invention relates to a mitochondrial targeting fluorescent probe as well as a synthesis method and application thereof. The mitochondrial targeting fluorescent probe (TPP-TPEDCH) is synthesized through a chemical reaction by taking a fluorescent molec
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Paragraph 0042; 0047
(2020/12/29)
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- Lysosome targeted photosensitizer, synthesis method and application in biological imaging
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The invention relates to a lysosome targeted photosensitizer as well as a synthesis method and application thereof in biological imaging. The lysosome targeted photosensitizer and (MP-TPEDCH) are formed by connecting MP as a lysosome targeted group and TP
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Paragraph 0042-0044; 0049
(2020/12/15)
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- Decarboxylation with Carbon Monoxide: The Direct Conversion of Carboxylic Acids into Potent Acid Triflate Electrophiles
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We report a new strategy for the conversion of carboxylic acids into potent acid triflate electrophiles. The reaction involves oxidative carbonylation of carboxylic acids with I2 in the presence of AgOTf, and is postulated to proceed via acyl hypoiodites that react with CO to form acid triflates. Coupling this chemistry with subsequent trapping with arenes offers a mild, room temperature approach to generate ketones directly from broadly available carboxylic acids without the use of corrosive and reactive Lewis or Bronsted acid additives, and instead from compounds that are readily available, stable, and functional group compatible.
- Kinney, R. Garrison,Arndtsen, Bruce A.
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supporting information
p. 5085 - 5089
(2019/04/01)
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- Synthesis of plasmodione metabolites and 13C-enriched plasmodione as chemical tools for drug metabolism investigation
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Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages. To investigate its metabolism, a series of plasmodione-based tools, including a fully 13C-labelled lead drug and putative metabolites, have been designed and synthesized for drug metabolism investigation. Furthermore, with the help of UHPLC-MS/MS, two of the drug metabolites have been identified from urine of drug-treated mice.
- Feng, Liwen,Lanfranchi, Don Antoine,Cotos, Leandro,Cesar-Rodo, Elena,Ehrhardt, Katharina,Goetz, Alice-Anne,Zimmermann, Herbert,Fenaille, Fran?ois,Blandin, Stephanie A.,Davioud-Charvet, Elisabeth
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p. 2647 - 2665
(2018/04/27)
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- Highly efficient photosensitizers with aggregation-induced emission characteristics obtained through precise molecular design
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We herein report a new strategy to obtain highly efficient photosensitizers (PSs) by reducing the singlet-triplet energy gap (ΔEST) and blocking the non-radiative decay pathways. Through precise molecular design, TP1-8 were synthesized to exhibit predictable properties including moderate to high photosensitizing efficacy, tunable absorption and emission wavelengths and aggregation-induced emission characteristics.
- Xu, Shidang,Wu, Wenbo,Cai, Xiaolei,Zhang, Chong-Jing,Yuan, Youyong,Liang, Jing,Feng, Guangxue,Manghnani, Purnima,Liu, Bin
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supporting information
p. 8727 - 8730
(2017/08/09)
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- Catalytic asymmetric alkylation of aryl heteroaryl ketones
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Tertiary diarylmethanols are highly bioactive structural motifs. A new strategy to access chiral tertiary diarylmethanols through copper-catalyzed direct alkylation of (di)(hetero)aryl ketones by using Grignard reagents was developed. The low reactivity a
- Ortiz, Pablo,Del Hoyo, Ana M.,Harutyunyan, Syuzanna R.
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supporting information
p. 72 - 76
(2015/02/19)
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- Synthesis of 2-acylthiophenes by palladium-catalyzed addition of thiophenes to nitriles
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A direct synthesis of 2-acylthiophenes has been developed through palladium-catalyzed addition of thiophenes to nitriles. The reaction proceeded well under the palladium(II) acetate/2,2'-bipyridine system and using d-(+)-camphorsulfonic acid as the additive. In addition, the obtained 2-acylthiophenes could undergo further coupling reactions to generate novel products.
- Jiang, Tao-Shan,Wang, Guan-Wu
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supporting information
p. 369 - 373
(2014/05/20)
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- Ligand-free Pd-catalyzed carbonylative cross-coupling reactions under atmospheric pressure of carbon monoxide: Synthesis of aryl ketones and heteroaromatic ketones
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The carbonylative Suzuki cross-coupling reactions of boronic acids with aryl iodides catalyzed by Pd2(dba)3 as a ligand-free catalyst under atmospheric pressure of carbon monoxide has been firstly developed. Under mild reaction conditions, a broad range of aryl/heteroaryl iodides and aryl/heteroaryl boronic acids were selectively coupled to afford the corresponding diaryl ketones in good to excellent yields at low catalyst loadings (0.05 to 2 mol-%). Moreover, the catalyst can also be recycled. The carbonylative Suzuki cross-coupling reactions of boronic acids with aryl iodides catalyzed by Pd2(dba)3 as a ligand-free catalyst under an atmosphere of carbon monoxide has been developed. A broad range of aryl/heteroaryl iodides and aryl/heteroaryl boronic acids were selectively coupled to afford the corresponding diaryl ketones in good to excellent yields. The catalyst can also be recycled.
- Li, Hongling,Yang, Min,Qi, Yanxing,Xue, Jijun
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supporting information; experimental part
p. 2662 - 2667
(2011/06/25)
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- Pd/C: An efficient, heterogeneous and reusable catalyst for phosphane-free carbonylative suzuki coupling reactions of aryl and heteroaryl iodides
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The carbonylative Suzuki coupling reaction of aryl boronic acid with different aryl and heteroaryl iodides was carried out to synthesize various unsymmetrical biaryl ketones by using Pd/C as an efficient, heterogeneous and reusable catalyst. The catalyst exhibits remarkable activity, and its reusability was tested up to four consecutive cycles. The reaction is applicable for various aryl and heteroaryl iodides having different steric and electronic properties. It provides good to excellent yield of the desired products. The developed protocol is advantageous with regard to the ease in handling the catalyst and the simple work-up procedure; it is also an environmentally benign process with effective catalyst recyclability. A facile protocol has been developed for the carbonylative Suzuki coupling reaction of aryl and heteroaryl iodides with Pd/C as effective, heterogeneous, reusable catalyst. The system is applicable for a wide variety of aryl and heteroaryl iodides. Copyright
- Khedkar, Mayur V.,Tambade, Pawan J.,Qureshi, Ziyauddin S.,Bhanage, Bhalchandra M.
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experimental part
p. 6981 - 6986
(2011/03/17)
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- Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition
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Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT2 receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT1 receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT2 selective agonist.
- Mahalingam,Wan, Yiqian,Murugaiah,Wallinder, Charlotta,Wu, Xiongyu,Plouffe, Bianca,Botros, Milad,Nyberg, Fred,Hallberg, Anders,Gallo-Payet, Nicole,Alterman, Mathias
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experimental part
p. 4570 - 4590
(2010/09/12)
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- Phosphane-free palladium-catalyzed carbonylative suzuki coupling reaction of aryl and heteroaryl iodides
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The carbonylative cross-coupling reaction of an arylboronic acid with an aryl iodide and a heteroaryl iodide to give unsymmetrical biaryl ketones was carried out by using Pd(tmhd)2/Pd (OAc)2 as a phosphane-free catalyst. Various aryl and heteroaryl iodides with different arylboronic acid derivatives provided, good, to excellent yields of the desired products under optimized reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.
- Tambade, Pawan J.,Patil, Yogesh P.,Panda, Anil G.,Bhanage, Bhalchandra M.
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experimental part
p. 3022 - 3025
(2009/11/30)
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- 5-Aryl-indan-1-ol and analogs useful as progesterone receptor modulators
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Compounds of formula I are provided, wherein R1-R9 and n are defined herein, and pharmaceutical compositions and kits containing these compounds. Also provided are methods of inducing contraception, providing hormone replacement ther
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Page/Page column 15
(2010/11/26)
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- 5-Aryl-indan-1-one and analogs useful as progesterone receptor modulators
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Compounds of formula I or II are provided, wherein R1—R8 are defined herein, and pharmaceutical compositions and kits containing these compounds. Also provides are methods of inducing contraception, providing hormone replacement ther
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Page/Page column 16
(2010/11/26)
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- NEW TRICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of formula (I), wherein the dotted lines, XI, X2, X3, X4, A, YI, Y2, Y3, Y4, ZI, Z2, R2 and R3
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- Infrared and Nuclear Magnetic Resonance Properties of Benzoyl Derivatives of Five-membered Monoheterocycles and Determination of Aromaticity Indices
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Benzophenones, 2-benzoylthiophenes, 2-benzoylpyrroles, and 2-benzoylfurans, which have substituents at m- and p-positions of the benzoyl ring were prepared and their ir and nmr spectra were obtained in 0.1 M chloroform-d solution. The chemical shift values of each series were plotted against the Hammett substituent parameters to give good correlation, with the exception of the ortho-Hs and -Cs. The slopes as well as the differences in chemical shift gave sets of meaningful values for the indices of aromaticy.
- Jeon, Kyu Ok,Jun, Jung Ho,Yu, Ji Sook,Lee, Chang Kiu
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p. 763 - 771
(2007/10/03)
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- Synthesis of Functionalized Styrenes via Palladium-Catalyzed Coupling of Aryl Bromides with Vinyl Tin Reagents
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Highly functionalized styrene derivatives have been synthesized in a single step by the palladium-catalyzed coupling of aryl bromides with tributylethenylstannane.Aryl bromides substituted with electron-withdrawing groups couple rapidly under the reaction conditions while bromides containing electron-donating substituents require further addition of catalyst for complete conversion. 1,4-Dibromobenzene can be coupled in a highly selective fashion with either 1 or 2 equiv of tin reagent to give 4-bromostyrene or diethenylbenzene, respectively.
- McKean, D. R.,Parrinello, G.,Renaldo, A. F.,Stille, J. K.
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p. 422 - 424
(2007/10/02)
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- Asymmetric Hydroformylation Catalyzed by Homogeneous and Polymer-Supported Platinum Complexes Containing Chiral Phosphine Ligands
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A complex of Pt(II) containing the chiral ligand (2S,4S)-N-(tert-butoxycarbonyl)-4-(diphenylphosphino)-2-pirrolidine in the presence of stannous chloride catalyzed the hydroformylation of a variety of prochiral olefins.Although the branched/normal (b/n) ratios were low (ca. 0.5), high ee's were achieved in the hydroformylation of styrene (70-80percent), p-isobutylstyrene (80percent), 2-vinylnaphthalene (77percent), 2-ethenyl-6-methoxynaphthalene (81percent), 4-(2-thienylcarbonyl)styrene (78percent), vinyl acetate(82percent), N-vinylphthalimide (73percent), methyl methacrylate (60percent), and norbornene (60percent).When the hydroformylation of styrene, 2-ethenyl-6-methoxynaphthalene, and vinyl acetate with PtCl2/SnCl2 was carried out in the presence of triethyl orthoformate, enantiomerically pure acetals were obtained.The hydroformylation in the presence of ethyl orthoformate also could be carried out by using a catalyst containing the PtCl2/SnCl2 complex bound to 60-μm beads composed of cross-linked polystyrene.
- Parrinello, Giovanni,Stille, J. K.
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p. 7122 - 7127
(2007/10/02)
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