- Design, synthesis, and preliminary biological evaluation of 3′,4′,5′-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents
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According to the pharmacophore combination principle, a set of new 3′,4′,5′-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1α, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
- Deng, Xiangping,Liu, Renbo,Li, Junjian,Li, Zhongli,Liu, Juan,Xiong, Runde,Lei, Xiaoyong,Zheng, Xing,Xie, Zhizhong,Tang, Guotao
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p. 1874 - 1884
(2019/01/28)
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- Selective Methylation of Arenes: A Radical C?H Functionalization/Cross-Coupling Sequence
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A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.
- Serpier, Fabien,Pan, Fei,Ham, Won Seok,Jacq, Jér?me,Genicot, Christophe,Ritter, Tobias
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p. 10697 - 10701
(2018/07/31)
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- INHIBITORS OF HEPATITIS C VIRUS POLYMERASE
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The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
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Paragraph 557; 558
(2016/10/11)
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- 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
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Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC 50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
- Zhi, Ying,Gao, Li-Xin,Jin, Yi,Tang, Chun-Lan,Li, Jing-Ya,Li, Jia,Long, Ya-Qiu
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p. 3670 - 3683
(2014/07/07)
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- Anion binding of N-(o-Methoxybenzamido)thioureas: Contribution of the intramolecular hydrogen bond in the N-benzamide moiety
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N-(o-Methoxybenzamido)- thioureas (2X/2Y) are found to show an enhanced anion binding affinity with binding constants over 107 mol -1L orders of magnitude for AcO- and a redshifted absorption of the anion binding complexes in acetonitrile (MeCN) relative to those of N-benzamidothioureas (1) that bear no o- OMe in the N-benzamide moiety, despite the electron-donating character of o-OMe. Absorption of the anion-2X/ 2Y complex was shown to be of the same charge-transfer nature as that of the anion-1 complex, but its dependence on substituent X is interestingly influenced by the o-MeO···HNC=O six-membered-ring intramolecular hydrogen bond identified in 2X/2Y. Such an intramolecular hydrogen bond is suggested to be responsible for the enhanced anion binding affinity. In the presence of this intramolecular hydrogen bond, the anion binding constant of 2X was found to be independent of substituent X at the N-phenyl ring, as in the case of 1, whereas that of 2Y showed an amplified dependence on substituent Y at the N′-phenyl ring, but to a lower extent than that of 1. A similar ring intramolecular hydrogen bond was purported to exist in 2Za, 2Zd, and 2Ze, which bear NHMe, F, and Cl as the ortho substituent in the N-benzamide moiety. In terms of the current roles of thiourea in not only anion recognition and sensing but also organocatalysis and crystal engineering, the present finding would be of significance for a wider structural diversity of smart thiourea derivatives with predesigned functions.
- Jiang, Qian-Qian,Darhkijav, Burenkhangai,Liu, Hao,Wang, Fang,Li, Zhao,Jiang, Yun-Bao
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experimental part
p. 543 - 549
(2010/08/20)
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- Design, synthesis and identification of novel colchicine-derived immunosuppressant
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Synthesis and biological evaluation of various colchicine analogues through the mixed-lymphocyte reaction (MLR), lymphoproliferation, and inhibitory effects on the inflammatory genes are described. In addition, a new series of immunosuppressive agents developed on the structural basis of colchicine, as well as their structure-activity relationships is reported. The most potent analogue 20a exhibited an excellent immunosuppressive activity on in vivo skin-allograft model, which is comparable to that of cyclosporin A.
- Chang, Dong-Jo,Yoon, Eun-Young,Lee, Geon-Bong,Kim, Soon-Ok,Kim, Wan-Joo,Kim, Young-Myeong,Jung, Jong-Wha,An, Hongchan,Suh, Young-Ger
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scheme or table
p. 4416 - 4420
(2010/04/05)
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- 8-OXOADENINE COMPOUND
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An 8-oxoadenine compound useful as an immuno-modulator having specific activity against Th1/Th2, specifically a prophylactic and therapeutic agent for a topical application for allergic diseases, viral siseases and cancers, which is represented by the following formula (1): , wherein A is a group of a formula represented by the formula (2): , wherein R2 is a substituted or unsubstituted alkyl group and so on, R3 is hydrogen atom or an alkyl group, R is a halogen atom and so on, n is 0-2, X1 is oxygen atom, Z is straight or branched chain alkylene, and R1 is an alkyl group which is optionally substituted by hydroxy group, an alkoxy group, alkoxycarbonyl group and so on, or its pharmaceutically acceptable salt.
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Page/Page column 144
(2010/11/24)
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- The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine
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A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.
- Paul, Tapas,Malachowski, William P.,Lee, Jisun
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p. 4007 - 4010
(2007/10/03)
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- NOVEL ADENINE COMPOUND AND USE THEREOF
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A drug for topically administration which is effective as an antiallergic agent. The drug for topically administration contains as an active ingredient an adenine compound represented by the general formula (1): [wherein ring A represents a 6 to 10 membered, mono or bicyclic, aromatic hydrocarbon or a 5 to 10 membered, mono or bicyclic, aromatic heterocycle containing one to three heteroatoms selected among 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; n is an integer of 0 to 2; m is an integer of 0 to 2; R represents halogeno, (un)substituted alkyl, etc.; X1 represents oxygen, sulfur, NR1 (R1 represents hydrogen or alkyl), or a single bond; Y1 represents a single bond, alkylene; etc.; Y2 represents a single bond, alkylene, etc.; Z represents alkylene; and at least one of Q1 and Q2 represents -COOR10 (wherein R10 represents (un)substituted alkyl, etc.), etc.] or a pharmaceutically acceptable salt of the compound.
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Page/Page column 28
(2010/02/12)
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- Structure-activity relationship studies of a bisbenzimidazole-based, Zn2+-dependent inhibitor of HCV NS3 serine protease
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A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn2+-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn2+-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn2+, with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.
- Yeung, Kap-Sun,Meanwell, Nicholas A.,Qiu, Zhilei,Hernandez, Dennis,Zhang, Sharon,McPhee, Fiona,Weinheimer, Steve,Clark, James M.,Janc, James W.
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p. 2355 - 2359
(2007/10/03)
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- The effect of an alkoxy group on the kinetic and thermodynamic acidity of benzene and toluene
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2-, 3- and 4-Methoxytoluene can be selectively metalated at an O-adjacent ortho position when butyllithium or tert-butyllithium in the presence of sodium (potassium) tert-butoxide or N,N,N',N'',N''-pentamethyldiethylenetriamine are employed as reagents. In contrast, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide deprotonate the benzylic α-position of 2- and 3-methoxytoaluene exclusively and of 4-methoxytoluene preferentially. These relative reactivities can be rationalized by an interplay of transition state stabilizing and destabilizing forces (dipole matching and metal coordination vs. lone pair repulsion).
- Schlosser, Manfred,Maccaroni, Paola,Marzi, Elena
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p. 2763 - 2770
(2007/10/03)
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- Design and Synthesis of New Naphthalenic Derivatives as Ligands for 2-Iodomelatonin Binding Sites
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New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)ethylamine.The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-(125I>iodomelatonin as the radioligand.Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor ( Ki = 8 +/- 0.2 nM ) for N-propionamide (3o).This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-propionamide (4b) ( Ki = 0.67 +/- 0.05 nM ) and N-cyclopropylformamide (Ki = 0.05 +/- 0.004 nM ( (4k).Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2.The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-γ-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.
- Langlois, Michel,Bremont, Beatrice,Shen, Shuren,Poncet, Annie,Andrieux, Jean,et al.
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p. 2050 - 2060
(2007/10/02)
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- Autorecycling System for the Specific 1,4-Reduction of α,β-Unsaturated Carbonyl Compounds Catalysed by 1,5-Dihydro-5-deazaflavin
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A useful autorecycling system for the specific 1,4-reduction of α,β-unsaturated carbonyl compounds to the corresponding saturated carbonyl compounds catalysed by a 10-aryl-5-deazaflavin in formic acid is reported.The specific reduction behaviour toward α,β-unsaturated carbonyl compounds is interpreted in terms of frontier molecular orbital theory (PM3 method).
- Nagamatsu, Tomohisa,Kuroda, Kazunori,Mimura, Norio,Yanada, Reiko,Yoneda, Fumio
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p. 1125 - 1128
(2007/10/02)
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