- Effect of chirality and redox potentials on the cytotoxicity of new ferrocene functionalized chiral tertiary amines
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Optically pure enantiomeric pair viz. ferrocene functionalized chiral tertiary amines S,S-(-)-1 and R,R-(+)-2 have been synthesized from ferrocenylmethylamine to probe the influence of chirality and the redox potential on their anti-proliferative activity. Compounds were characterized by microanalysis, HPLC, 1H, 13C NMR, UV-visible, fluorescence, FTIR, thermogravimetric and crystallographic techniques. The single crystal X-ray diffraction (SCXRD) study revealed that the molecules of 1 holding S,S-chirality at benzylic carbons forms a fascinating M-helix while 2 holding R,R-chirality at benzylic carbons forms P-helix by involving intra- and intermolecular H-bonding interactions as verified by Hirshfeld surface analysis. Chirality-related influence was observed on the antiproliferative activity of enantiomeric pair and at the supramolecular level. For instance, enantiomer R,R-(+)-2 is found to be highly active against all the investigated human carcinoma cell lines MCF 7, IMR 32, HepG2, and immortal L132 cell lines. In particular, R,R-(+)-2 exhibited more than 10 folds better antiproliferation (IC 50: 6.35±0.19 μM) than other enantiomer S,S-(-)-1 (IC50: 65.96 ± 0.12 μM) and four folds better activity than highly successful anticancer drug, cisplatin (IC50: 24.3 ± 1.7 μM) against Hep G2 cell line. The electrochemical, DFT calculations and molecular docking study have been performed to justify the experimental outcomes.
- Roy, Hetal,Savani, Chirag J.,Singh, Vinay K.,Vennapu, Dushyanth R.
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- Synthetic Models of Quasi-Stable Amyloid β40 Oligomers with Significant Neurotoxicity
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The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids. Here, we describe the synthesis and characterization of three dimer models of the toxic-conformation constrained E22P-Aβ40 using l,l-2,6-diaminopimeric acid (DAP) or l,l-2,8-diaminoazelaic acid (DAZ) linker at position 30, which is incorporated into the intermolecular parallel β-sheet region, and DAP at position 38 in the C-terminal hydrophobic core. E22P-A30DAP-Aβ40 dimer (1) and E22P-A30DAZ-Aβ40 dimer (2) existed mainly in oligomeric states even after 2 weeks incubation without forming fibrils, unlike the corresponding monomer. Their neurotoxicity toward SH-SY5Y neuroblastoma cells was very weak. In contrast, E22P-G38DAP-Aβ40 dimer (3) formed β-sheet-rich oligomeric aggregates, and exhibited more potent neurotoxicity than the corresponding monomer. Ion mobility-mass spectrometry suggested that high molecular-weight oligomers (12-24-mer) of 3 form, but not for 1 and 2 after 4 h incubation. These findings indicate that formation of the hydrophobic core at the C-terminus, rather than intermolecular parallel β-sheet, triggers the formation of toxic Aβ oligomers. Compound 3 may be a suitable model for studying the etiology of Alzheimer's disease.
- Irie, Yumi,Murakami, Kazuma,Hanaki, Mizuho,Hanaki, Yusuke,Suzuki, Takashi,Monobe, Yoko,Takai, Tomoyo,Akagi, Ken-Ichi,Kawase, Taiji,Hirose, Kenji,Irie, Kazuhiro
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p. 807 - 816
(2017/04/26)
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- Using chiral ionic liquid additives to enhance asymmetric induction in a Diels-Alder reaction
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A bis-oxazoline ligand has been complexed using Cu(ii) and Zn(ii) trifluoromethanesulfonate and a range of chiral ionic liquid (CIL) additives based on natural products were used as a co-catalyst for a Diels-Alder reaction. The catalytic performance of th
- Goodrich,Nimal Gunaratne,Hall,Wang,Jin,Muldoon,Ribeiro,Pombeiro,Parvulescu,Davey,Hardacre
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supporting information
p. 1704 - 1713
(2017/02/10)
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- Efficient stereocontrolled synthesis of sitagliptin phosphate
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The synthesis of sitagliptin phosphate 1, a novel DPP-IV inhibitor for the treatment of type 2 diabetes mellitus has been accomplished starting from the chiral synthon (1,4-bis[(R)-1-phenylethyl]piperazine-2,5-dione) 2, involving highly stereocontrolled (>98%) alkylation as a key step, in a good overall yield of 50% over six steps.
- Subbaiah,Haq, Wahajul
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p. 1026 - 1030
(2014/08/18)
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- Discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening
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Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3. In this study, nearly 204,000 compounds in Specs database were screened by virtual screening, and samples of top 100 compounds identified as candidate small-molecule inhibitors of STAT3 were evaluated by STAT3-dependent luciferase reporter assay as well as other cell-based assays. A benzothiazole core scaffold containing compound, 9, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 3.567 μM. It is the first time to discover benzothiazole scaffold as a potent STAT3 signaling inhibitor. We further investigated the (structure-activity relationship) SAR of the benzothiazole analogues, and discovered compound 16w as a better small-molecule inhibitor. Both compounds inhibited the phosphorylation of STAT3 and had no obvious effect on upstream JAK2 kinase.
- Zhang, Mingming,Zhu, Weiliang,Li, Yingxia
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p. 301 - 310
(2013/05/22)
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- PYRIDYL-AZA(THIO)XANTHONE SENSITIZER COMPRISING LANTHANIDE(III) ION COMPLEXING COMPOUNDS, THEIR LUMINESCENT LANTHANIDE (III) ION COMPLEXES AND USE THEREOF AS FLUORESCENT LABELS.
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Lanthanide (III) Ion completing compound comprising: (1) a sensitizer moiety of Formula (I) in which: a is an integer from 1 to 4; b is an integer equal to 1 or 2; c is an integer equal to 1 or 2; (R1)a, (R2)b, (R3)C are t
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Page/Page column 47
(2010/08/08)
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- Modular synthesis of heterocyclic carbene precursors
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A series of N-heterocyclic carbene precursors, containing an imidazoline or tetrahydropyrimidine framework, were prepared from ω-chloroalkanoyl chlorides. The sequential attachment of nitrogen nucleophiles and subsequent ring closure gave, depending on the reagents used, either the desired dihydroimidazolium and tetrahydropyrimidinium salts or their parent heterocycles. In this latter case, the second substituent was introduced in an alkylation step. The preparation of carbene precursors bearing chiral or bulky substituents was achieved with comparable efficiency.
- Paczal, Attila,Benyei, Attila C.,Kotschy, Andras
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p. 5969 - 5979
(2007/10/03)
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- A selective one-step synthesis of tris N-alkylated cyclens
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A general one-step synthesis for tris N-alkylated cyclens with good yield and unprecedented selectivity is presented. Tris and 1,4-bis N-alkylated cyclens, as the only two major products are isolated. Furthermore, according to the single crystal X-ray str
- Li, Cong,Wong, Wing-Tak
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p. 5595 - 5601
(2007/10/03)
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS
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Disclosed are novel heterocyclic derivatives, useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.
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- Novel synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones
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A novel and effective synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones via Smiles rearrangement is presented. Treatment of N-substituted 2-chloro(or hydroxy)acetamide, 2-tetrahydropyranyl-4-chloro-5-hydroxy(or chloro)pyridazin-3-one and cesium carbonate in refluxing acetonitrile was afforded the corresponding pyridazino[4,5-b][1,4]oxazin-3,8-diones in excellent yield.
- Cho, Su-Dong,Song, Sang-Yong,Park, Yong-Dae,Kim, Jeum-Jong,Joo, Woo-Hong,Shiro, Motoo,Falck,Shin, Dong-Soo,Yoon, Yong-Jin
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p. 8995 - 8998
(2007/10/03)
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- Synthesis, characterisation and application of lanthanide cyclen complexes in organic synthesis
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Hexadentate cyclen complexes of Sm(III), Eu(III) and Yb(III) have been prepared from 1,4-bis[(R)-α-methylbenzyl-aminocarbonylmethyl]-1,4,7, 10-tetraazacycldodecane and characterised. The crystal structures of the isomorphous complexes of Eu(III) and Sm (I
- Batsanov, Andrei S.,Bruce, James I.,Ganesh, Thota,Low, Paul J.,Kataky, Ritu,Puschmann, Horst,Steel, Patrick G.
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p. 932 - 937
(2007/10/03)
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- Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
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The present invention provides compounds, and pharmaceutical compositions containing those compounds, that are active at metabotropic glutamate receptors. The compounds are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.
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- Synthesis, time-resolved luminescence, nmr spectroscopy, circular dichroism and circularly polarised luminescence studies of enantiopure macrocyclic lanthanide tetraamide complexes
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The syntheses and properties of a series of lanthanide complexes (Ln = Eu, Tb, Dy, Yb) of C4 symmetric chiral tetraamide ligands based on 1,4,7,10- tetraazacyclododecane are reported. The configuration of the chiral centre at carbon in the amid
- Dickins, Rachel S.,Howard, Judith A.K.,Maupin, Christine L.,Moloney, Janet M.,Parker, David,Riehl, James P.,Siligardi, Giuliano,Williams, J.A. Gareth
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p. 1095 - 1105
(2007/10/03)
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- Luminescent sensors for pH, pO2, halide and hydroxide ions using phenanthridine as a photosensitiser in macrocyclic europium and terbium complexes
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The metal-based luminescence of the Eu and Tb complexes of the octadentate ligands L1 and L2a/2b is a function of pH in aqueous solution:in [EuL1], the red-emission is switched on following N-protonation of the sensitising
- Parker, David,Senenayake, P. Kanthi,Williams, G. A. Gareth
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p. 2129 - 2140
(2007/10/03)
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