36258-79-4Relevant academic research and scientific papers
Monitoring penetratin interactions with lipid membranes and cell internalization using a new hydration-sensitive fluorescent probe
Zamotaiev, Oleksandr M.,Postupalenko, Viktoriia Y.,Shvadchak, Volodymyr V.,Pivovarenko, Vasyl G.,Klymchenko, Andrey S.,Mely, Yves
, p. 7036 - 7044 (2014)
A new fluorescent label N-[4′-(dimethylamino)-3-hydroxyflavone-7-yl]- N-methyl-β-alanine (7AF) was synthesized. Due to two electron donor groups at the opposite ends of the chromophore, an excited state intramolecular proton transfer (ESIPT) resulting in a dual emission was observed even in highly polar media and its fluorescence quantum yield was found to be remarkably high in a broad range of solvents including water. As a consequence, this label exhibits a remarkable sensitivity to the hydration of its environment, which is observed as a color switch between the emission of the ESIPT product (T* form) and that of the normal N* form. The 7AF label was coupled to the N-terminus of penetratin, a cell penetrating peptide, in order to study its interactions with lipid membranes and internalization inside the cells. As expected, the binding of penetratin to lipid membranes resulted in a dramatic switch in the relative intensity of its two emission bands as compared to its emission in buffer. Our studies with different lipid compositions confirmed the preference of penetratin to lipid membranes of the liquid disordered phase. After incubation of low concentrations of labeled penetratin with living cells, ratiometric imaging revealed, in addition to membrane-bound species, a significant fraction of free peptide in cytosol showing the characteristic emission from aqueous medium. At higher concentrations of penetratin, mainly peptides bound to cell membrane structures were observed. These observations confirmed the ability of penetratin to enter the cytosol by direct translocation through the cell plasma membrane, in addition to the classical entry by endocytosis. The present probe constitutes thus a powerful tool to study the interaction of peptides with living cells and their internalization mechanisms. This journal is the Partner Organisations 2014.
Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy
Zhao, Chenxi,Tang, Chu,Li, Changhao,Ning, Wentao,Hu, Zhiye,Xin, Lilan,Zhou, Hai-Bing,Huang, Jian
, (2021/05/10)
Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.
Amide conformational switching induced by protonation of aromatic substituent
Yamasaki, Ryu,Tanatani, Aya,Azumaya, Isao,Saito, Shoichi,Yamaguchi, Kentaro,Kagechika, Hiroyuki
, p. 1265 - 1267 (2007/10/03)
(Matrix presented) Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the ratio correlates well with the Hammett σ values of the substituents. These steric properties can be applied to achieve amide conformational swiching by protonation at the aromatic substituent of 4-[bis(dimethylamino)]-N-methylacetanilide or N-[p-(dimethylamino)phenyl]-N-phenylacetamide.
New Antiallergic Pyranoquinoline-2,8-dicarboxylic Acids with Potential for the Topical Treatment of Asthma
Cairns, Hugh,Cox, David,Gould, Ken J.,Ingall, Anthony H.,Suschitzky, John L.
, p. 1832 - 1842 (2007/10/02)
A nimber of antiallergic pyranoquinolinedicarboxylic acid derivatives with potential for the topical treatment of asthma have been synthesized.All the compounds have been evaluated against rat passive cutaneous anaphylaxis and in a dog hypotension screen.This is the first detailed description of the application of the latter screen for the identification of antiallergic agents.Two compounds, disodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranoquinoline-2,8-dicarboxylate (86) and disodium 6-(methylamino)-4-oxo-10-propyl-4H-pyranoquinoline-2,8-dicarboxylate (72), were selected and further evaluated for their ability to induce phosphorylation of a 78000 molecular weight protein associated with the rat peritoneal mast cell.Their ability to inhibit histamine release from these cells and from a mucosal mast cell preparation has also been evaluated.These compounds, nedocromil sodium (TILADE 86) and minocromil (the free acid of 72), are at present undergoing therapeutic evaluation.The rationale for the screening procedure and the relevance of the second carboxylic acid function of these dibasic acids to receptor binding are discussed.
