57260-71-6Relevant academic research and scientific papers
Polystyrene-Based Deblocking-Scavenging Agents for the 9-Fluorenylmethyloxycarbonyl Amino-Protecting Group
Carpino, Louis A.,Mansour, E. M. E.,Cheng, C. H.,Williams, James R.,MacDonald, Russell,et al.
, p. 661 - 665 (1983)
Piperazino- and piperidino-functionalized polystyrenes have been examined as deblocking-scavenging agents for the 9-fluorenylmethyloxycarbonyl (Fmoc) amino-protecting group.Both commercial and synthesized polystyrenes have been used as supports.In order to introduce the active functional groups, (chloromethyl)polystyrene 2 was treated with tert-butyl piperazine-1-carboxylate followed by acidic deblocking (HCl/dioxane) or, alternatively, was directly aminated by means of 10 molar excess of piperazine or 1,3-bis(4-piperidino)propane.Compounds 7-9 were examined as cross-linking agents in the preparation of appropriate reagents.Most suitable were reagents prepared from commercial macroreticular resins (XE-305) or those cross-linked via DVT (8).Proof that the DBF liberated in the deblocking prozess was scavenged (partially) by the active secondary amine reagents 4 came from (a) a study of the successful regeneration of an active agent from 5 by treatment with alkali (H2O-dioxane) and (b) liberation of 9-methylfluorene from 5 by hydrogenation (NH4OCHO/Pd-C).
Small-Molecule Inhibition of the UNC-Src Interaction Impairs Dynamic Src Localization in Cells
Garivet, Guillaume,Hofer, Walter,Konitsiotis, Antonios,Klein, Christian,Kaiser, Nadine,Mejuch, Tom,Fansa, Eyad,Alsaabi, Rania,Wittinghofer, Alfred,Bastiaens, Philippe I.H.,Waldmann, Herbert
, p. 842 - 7,851 (2019)
Interference with the signaling activity of the N-myristoylated nonreceptor protein tyrosine kinase Src is considered a viable approach in anti-cancer drug discovery. However, ATP-competitive Src inhibitors have not reached the clinic yet and alternative approaches are in high demand. The UNC119A/B proteins bind the myristoylated N terminus of Src and thereby mediate energy-driven spatial cycles that maintain Src enrichment at the plasma membrane, which is critical for Src signaling activity. We describe the discovery of a potent and specific inhibitor of the UNC119-Src interaction with unprecedented chemotype. The inhibitor binds to UNC119 in cells, and induces redistribution of Src to endomembranes and reduction of activating Src autophosphorylation on Y419. UNC119 inhibition in Src-dependent colorectal cancer cells results in the specific reduction of cell growth and clonogenic potential. Our results demonstrate that small-molecule interference with the dynamics of the Src spatial cycle may provide an opportunity to impair oncogenic Src signaling. Garivet et al. discovered a small-molecule UNC119-Src interaction inhibitor, which interferes with Src enrichment at the plasma membrane and reduces clonogenic potential and growth of Src-dependent cells. Small molecule interference with the dynamics of cellular Src localization may provide an alternative approach to target oncogenic Src.
Carbamates as potential prodrugs and a new warhead for HDAC inhibition
King, Kristina,Hauser, Alexander-Thomas,Melesina, Jelena,Sippl, Wolfgang,Jung, Manfred
, (2018)
We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6-selective inhibitor bufexamac.
Conjugating a groove-binding motif to an Ir(iii) complex for the enhancement of G-quadruplex probe behavior
Wang, Modi,Mao, Zhifeng,Kang, Tian-Shu,Wong, Chun-Yuen,Mergny, Jean-Louis,Leung, Chung-Hang,Ma, Dik-Lung
, p. 2516 - 2523 (2016)
In this study, the reported G-quadruplex groove binder benzo[d,e]isoquinoline was linked to a cyclometallated Ir(iii) complex to generate a highly selective DNA probe 1 that retains the favorable photophysical properties of the parent complex. The linked complex 1 showed advantages of both parent complex 2 and groove binder 3. Similar to 3, the conjugated complex 1 exhibits a superior affinity and selectivity for G-quadruplex DNA over other conformations of DNA or proteins, with the fold enhancement ratio obviously improved compared with parent complex 2. The molecular modelling revealed a groove-binding mode between complex 1 and G-quadruplex. Meanwhile 1 also possesses the prominent advantages of transition metal complex probes such as a large Stokes shift and long lifetime phosphorescence, which could be recognized in strong fluorescence media through time-resolved emission spectroscopy (TRES). We then employed 1 to develop a detection assay for AGR2, a potential cancer biomarker, as a "proof-of-principle" demonstration of the application of a linked complex for DNA-based detection in diluted fetal bovine serum. We anticipate that this conjugation method may be further employed in the development of DNA probes and have applications in label-free DNA-based diagnostic platforms.
Synthesis of new soluble dendrimers on poly(ethylene glycole) sublayer
Lu,Xie,Chen,Yang
, p. 788 - 791 (2009)
A rational method of synthesis was developed for new soluble dendrimers on poly(ethylene glycole) sublayer with a high density of functional groups applying 2,4,6-trichloro-1,3,5-triazine as a dendron and piperazine as linker and functional group carrier. The density of functional groups in the synthesized soluble dendrimers calculated from the elemental analysis for chlorine was 2.19 mmol of NH groups per 1 g of polymer. These new water-soluble dendrimers can be used not only as convenient soluble polymer sublayers but also for efficient trapping in purification of reaction products from impurities.
Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis
Av-Gay, Yossef,Imming, Peter,Narula, Gagandeep,Richter, Adrian,Rudolph, Ines,Wagner, Christoph,Seidel, Rüdiger W.
supporting information, (2021/12/27)
8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.
Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity
Nunes, Paulo Sérgio Gon?alves,da Silva, Gabriel,Nascimento, Sofia,Mantoani, Susimaire Pedersoli,de Andrade, Peterson,Bernardes, Emerson Soares,Kawano, Daniel Fábio,Leopoldino, Andreia Machado,Carvalho, Ivone
supporting information, (2021/05/26)
ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 μM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.
Synthesis of Azocanes from Piperidines via an Azetidinium Intermediate
Leverenz, Malte,Masson, Guillaume,Pardo, Domingo Gomez,Cossy, Janine
supporting information, p. 16325 - 16328 (2021/10/25)
α-Trifluoromethyl azocanes are accessible from 2-(trifluoropropan-2-ol) piperidines by metal-free ring-expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo-halides) with an excellent regio- diastereo- and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.
Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists
Budde, Thomas,Grey, Lucie,Heitman, Laura H.,Hundehege, Petra,Isaak, Andreas,Junker, Anna,Koch, Oliver,Michetti, Lucia,Patberg, Marius,Schulte, Janine,Vinnenberg, Laura,van der Horst, Cas,Füsser, Friederike,Ortiz Zacarías, Natalia V.
, (2021/09/28)
The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC50 values of 5.7–7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.
Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine
Manickam, Manoj,Boggu, Pulla Reddy,Pillaiyar, Thanigaimalai,Nam, Yeo Jin,Abdullah, Md.,Lee, Seung Jin,Kang, Jong Seong,Jung, Sang-Hun
supporting information, (2020/12/03)
In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in μM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.
