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11.
Beatriz F. dos Santos Caroline F. Pereira Mikaela P. Pinz Aline R. de Oliveira George Brand Ramesh Katla Ethel A. Wilhelm Cristiane Luchese Nelson L.C. Domingues 《应用有机金属化学》2020,34(7):e5650
Functionalization of 2,1,3-benzothiadiazole (BTD) with thiols at C-5 position remains low explored. Moreover, the arylthiol-substitutions at this position are also unexplored and can not be found by a SN2 or SN1 reaction. In this sense, herein we present a new palladium-catalyzed methodology for a wide variety of unpublished 5-arylsulfanyl-benzo-2,1,3-thiadiazole derivatives synthesis with moderate to high yields using a low catalytic loading of Pd(L-Pro)2 as low-coast, and efficient catalyst in low reaction time. Besides, we concluded that the pKa of thiol species has an important role in this catalysis, mainly in the CMD like catalytic cyclo process, which strongly interferes in the reaction yields. Furthermore, arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives have been assessed (in vitro) as potential acetylcholinesterase inhibitors. 相似文献
12.
Dr. Kalaiselvi Natarajan Daniel Müller-Klieser Stefan Rubner Prof. Dr. Thorsten Berg 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(1):148-154
We present a new approach for the identification of inhibitors of phosphorylation-dependent protein–protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening. From a database of 10 369 180 compounds, we identified 85 021 natural product-derived phenolic fragments, which were virtually O-phosphorylated and screened for in silico binding to the STAT3 SH2 domain. Nine screening hits were then synthesized, eight of which showed a degree of in vitro inhibition of STAT3. After analysis of its selectivity profile, the most potent inhibitor was then developed to Stafia-1, the first small molecule shown to preferentially inhibit the STAT family member STAT5a over the close homologue STAT5b. A phosphonate prodrug based on Stafia-1 inhibited STAT5a with selectivity over STAT5b in human leukemia cells, providing the first demonstration of selective in vitro and intracellular inhibition of STAT5a by a small-molecule inhibitor. 相似文献
13.
Kanna Adachi Tomoshi Yamada Hayate Ishizuka Mana Oki Shunsuke Tsunogae Noriko Shimada Osamu Chiba Tatsuya Orihara Prof. Dr. Masafumi Hidaka Prof. Dr. Takatsugu Hirokawa Dr. Minami Odagi Prof. Dr. Keiichi Konoki Prof. Dr. Mari Yotsu-Yamashita Prof. Dr. Kazuo Nagasawa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):2025-2033
A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717. 相似文献
14.
Niklas Jänsch Wisely Oki Sugiarto Marius Muth Aleksandra Kopranovic Charlotte Desczyk Matthias Ballweg Frank Kirschhöfer Dr. Gerald Brenner-Weiss Prof. Dr. Franz-Josef Meyer-Almes 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(58):13249-13255
Human histone deacetylase 8 is a well-recognized target for T-cell lymphoma and particularly childhood neuroblastoma. PD-404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys102 and Cys153. This study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD-404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges. 相似文献
15.
Dr. Jan Nekvinda Michael Kugler Dr. Josef Holub Dr. Suzan El Anwar Dr. Jiří Brynda Klára Pospíšilová Dr. Zdeňka Růžičková Dr. Pavlína Řezáčová Dr. Bohumír Grüner 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(69):16541-16553
Carbonic anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closo-dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with a different geometric position of carbon atoms. The closo-compounds from the ortho- and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1−) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant (Ki) and selectivity towards CA IX. Decreasing trends in Ki and selectivity index (SI) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity. 相似文献
16.
Kevin Doyle Maxine Roberts Jenna Harvey Richard Hewer Matthias Zebisch Victor Rangel Meigang Gu Yiming Wu Lichao Yang Mark Carlton Lee Dawson Roland Bürli 《Helvetica chimica acta》2023,106(9):e202300080
Brain concentrations of nicotinamide adenine dinucleotide (NAD+), an important cellular co-factor, tend to decrease with age and in neurodegeneration. As the NADase cluster of differentiation 38 (CD38) significantly contributes to NAD+ consumption, we reasoned that CD38 inhibition may be of therapeutic value for CNS disorders. The new pyrazole compound was designed based on a known CD38 inhibitor and showed good inhibitory potency. Several attempts to co-crystallise this pyrazole with CD38 and cyclic adenosine diphosphate ribose (cADPR) culminated in a high-resolution X-ray structure, in which the pyrazolyl group in the new compound formed a covalent bond with one of the ribosyl units of cADPR. This reaction proceeded under retention of configuration and resulted in a neutral ribosyl-pyrazole conjugate that is embedded within the active site of the enzyme. An analysis of this structural complex gave rise to design principles that enabled the preparation of more potent CD38 inhibitors with drug-like properties. 相似文献
17.
Synthesis and Biological Evaluation of Several Dephosphonated Analogues of CMP‐Neu5Ac as Inhibitors of GM3‐Synthase 下载免费PDF全文
Dr. Paola Rota Dr. Federica Cirillo Dr. Marco Piccoli Dr. Antonio Gregorio Prof. Guido Tettamanti Prof. Pietro Allevi Prof. Luigi Anastasia 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(41):14614-14629
Previous studies demonstrated that reducing the GM3 content in myoblasts increased the cell resistance to hypoxic stress, suggesting that a pharmacological inhibition of the GM3 synthesis could be instrumental for the development of new treatments for ischemic diseases. Herein, the synthesis of several dephosphonated CMP‐Neu5Ac congeners and their anti ‐ GM3‐synthase activity is reported. Biological activity testes revealed that some inhibitors almost completely blocked the GM3‐synthase activity in vitro and reduced the GM3 content in living embryonic kidney 293A cells, eventually activating the epidermal growth factor receptor (EGFR) signaling cascade. 相似文献
18.
Light‐Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy 下载免费PDF全文
Dr. Wiktor Szymanski Maria E. Ourailidou Dr. Willem A. Velema Prof. Dr. Frank J. Dekker Prof. Dr. Ben L. Feringa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(46):16517-16524
Cancer treatment suffers from limitations that have a major impact on the patient’s quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy. 相似文献
19.
Cover Picture: A Modular Synthesis of Conformationally Preorganised Extended β‐Strand Peptidomimetics (Chem. Eur. J. 42/2015) 下载免费PDF全文
20.
Inside Back Cover: Fragment‐Based Discovery of a Dual pan‐RET/VEGFR2 Kinase Inhibitor Optimized for Single‐Agent Polypharmacology (Angew. Chem. Int. Ed. 30/2015) 下载免费PDF全文