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51.
Katherine M. Byrd Chitra Subramanian Jacqueline Sanchez Hashim F. Motiwala Weiya Liu Prof. Mark S. Cohen Prof. Jeffrey Holzbeierlein Prof. Brian S. J. Blagg 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(20):6921-6931
Development of heat shock protein 90 (Hsp90) C‐terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°. 相似文献
52.
Dr. Xavier Just-Baringo Alejandro Yeste-Vázquez Javier Moreno-Morales Dr. Clara Ballesté-Delpierre Prof. Jordi Vila Prof. Ernest Giralt 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(51):12987-12991
The introduction of a novel tetra-ortho-chloroazobenzene amino acid (CEBA) has enabled photoswitching of the antimicrobial activity of tyrocidine A analogues by using exclusively visible light, granting spatiotemporal control under benign conditions. Compounds bearing this photoswitchable amino acid become active upon irradiation with red light, but quickly turn-off upon exposure to other visible light wavelengths. Critically, sunlight quickly triggers isomerisation of the red light-activated compounds into their original trans form, offering an ideal platform for self-deactivation upon release into the environment. Linear analogues of tyrocidine A were found to provide the best photocontrol of their antimicrobial activity, leading to compounds active against Acinetobacter baumannii upon isomerisation. Exploration of their N- and C-termini has provided insights into key elements of their structure and has allowed obtaining new antimicrobials displaying excellent strain selectivity and photocontrol. 相似文献
53.
Sridevi V. Shinde Sarika Sinha Prof. Dr. Kumaravel Somasundaram Prof. Dr. Ashoka G. Samuelson 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(39):12278-12291
Neutral half‐sandwich organometallic ruthenium(II) complexes of the type [(η6‐cymene)RuCl2(L)] ( H1 – H10 ), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single‐crystal X‐ray diffraction confirming a piano‐stool geometry with η6 coordination of the arene ligand. Hydrogen bonding between the N? H group of the heterocycle and a chlorine atom attached to Ru stabilizes the metal–ligand interaction. Complexes coordinated to a mercaptobenzothiazole framework ( H1 ) or mercaptobenzoxazole ( H6 ) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1‐phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non‐intercalative fashion and cause unwinding of plasmid DNA in a cell‐free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIα activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen‐bond donor on the heterocycle reduces the cytotoxicity. 相似文献
54.
Dr. Ruth Matesanz Dr. José Fernando Diaz Dr. Francisco Corzana Andrés G. Santana Dr. Agatha Bastida Dr. Juan Luis Asensio 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(10):2875-2889
The most common mode of bacterial resistance to aminoglycoside antibiotics is the enzyme‐catalysed chemical modification of the drug. Over the last two decades, significant efforts in medicinal chemistry have been focused on the design of non‐ inactivable antibiotics. Unfortunately, this strategy has met with limited success on account of the remarkably wide substrate specificity of aminoglycoside‐modifying enzymes. To understand the mechanisms behind substrate promiscuity, we have performed a comprehensive experimental and theoretical analysis of the molecular‐recognition processes that lead to antibiotic inactivation by Staphylococcus aureus nucleotidyltransferase 4′(ANT(4′)), a clinically relevant protein. According to our results, the ability of this enzyme to inactivate structurally diverse polycationic molecules relies on three specific features of the catalytic region. First, the dominant role of electrostatics in aminoglycoside recognition, in combination with the significant extension of the enzyme anionic regions, confers to the protein/antibiotic complex a highly dynamic character. The motion deduced for the bound antibiotic seem to be essential for the enzyme action and probably provide a mechanism to explore alternative drug inactivation modes. Second, the nucleotide recognition is exclusively mediated by the inorganic fragment. In fact, even inorganic triphosphate can be employed as a substrate. Third, ANT(4′) seems to be equipped with a duplicated basic catalyst that is able to promote drug inactivation through different reactive geometries. This particular combination of features explains the enzyme versatility and renders the design of non‐inactivable derivatives a challenging task. 相似文献
55.
Apurva Pandey Dr. Eszter Boros 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(26):7340-7350
Drug discovery aimed at the efficient eradication of life-threatening bacterial infections, especially in light of the emergence of multi-drug resistance of pathogenic bacteria, has remained a challenge for medicinal chemists over the past several decades. As nutrient acquisition and metabolism at the host-pathogen interface become better elucidated, new drug targets continue to emerge. Metal homeostasis is among these processes, and thus provides opportunities for medicinal inorganic chemists to alter or disrupt these processes selectively to impart bacteriostatic or bacteriotoxic effects. In this minireview, we showcase some of the recent work from the field of metal-based antibacterial agents and highlight divergent strategies and mechanisms of action. 相似文献
56.
《应用有机金属化学》2017,31(9)
Because of the side effects and drug resistance of cisplatin, a basic clinically approved chemotherapeutic drug, a new attempt is reported to develop a novel antitumor drug based on complexation of iron metal ion with organic moiety that may be effective and safer. A newly synthesized iron(III) diacetylmonoxime‐2‐hydrazinopyridine complex was tested firstly for its cytotoxicity and superoxide dismutase (SOD)‐mimic activity in vitro then for its antitumor activity against Ehrlich ascites carcinoma (EAC) and the related biochemical alterations in vivo in comparison with cisplatin. The complex showed 80.88% SOD‐mimic activity and IC50 of 2.6 μg ml−1. In EAC‐bearing mice, in a dose‐dependent manner, Fe(III) complex treatment exhibited significant hematological profile improvements, tumor volume, viable cell count and hepatic lipid peroxidation level decreases, life span extension, hepatic glutathione and total antioxidant capacity levels enhancements, hepatic SOD and catalase activities augmentations, liver function tests alterations attenuations, and hepatocyte nucleic acids content normalization. Thus, the Fe(III) diacetylmonoxime‐2‐hydrazinopyridine complex is a novel, promising, less toxic antitumor agent. Its killing of tumor cells may be via a reactive oxygen species scavenging mechanism. 相似文献
57.
In Situ Proteome Profiling and Bioimaging Applications of Small‐Molecule Affinity‐Based Probes Derived From DOT1L Inhibitors 下载免费PDF全文
Biwei Zhu Dr. Hailong Zhang Sijun Pan Chenyu Wang Dr. Jingyan Ge Prof. Dr. Jun‐Seok Lee Prof. Dr. Shao Q. Yao 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(23):7824-7836
DOT1L is the sole protein methyltransferase that methylates histone H3 on lysine 79 (H3K79), and is a promising drug target against cancers. Small‐molecule inhibitors of DOT1L such as FED1 are potential anti‐cancer agents and useful tools to investigate the biological roles of DOT1L in human diseases. FED1 showed excellent in vitro inhibitory activity against DOT1L, but its cellular effect was relatively poor. In this study, we designed and synthesized photo‐reactive and “clickable” affinity‐based probes (AfBPs), P1 and P2 , which were cell‐permeable and structural mimics of FED1 . The binding and inhibitory effects of these two probes against DOT1L protein were extensively investigated in vitro and in live mammalian cells (in situ). The cellular uptake and sub‐cellular localization properties of the probes were subsequently studied in live‐cell imaging experiments, and our results revealed that, whereas both P1 and P2 readily entered mammalian cells, most of them were not able to reach the cell nucleus where functional DOT1L resides. This offers a plausible explanation for the poor cellular activity of FED1 . Finally with P1 / P2 , large‐scale cell‐based proteome profiling, followed by quantitative LC‐MS/MS, was carried out to identify potential cellular off‐targets of FED1 . Amongst the more than 100 candidate off‐targets identified, NOP2 (a putative ribosomal RNA methyltransferase) was further confirmed to be likely a genuine off‐target of FED1 by preliminary validation experiments including pull‐down/Western blotting (PD/WB) and cellular thermal shift assay (CETSA). 相似文献
58.
Prof. Miguel A. Sierra Prof. Luis Casarrubios Dr. María C. de la Torre 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(30):7232-7242
Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new antibacterial drugs. Bio-organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well-characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio-organometallic derivatives of these drugs, as well as examples of the use of structure–activity relation (SAR) studies to increase the activity and to understand the mode of action of bio-organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio-organometallic mimics is presented in this article. 相似文献
59.
A One‐Pot Synthesis of N‐Aryl‐2‐Oxazolidinones and Cyclic Urethanes by the Lewis Base Catalyzed Fixation of Carbon Dioxide into Anilines and Bromoalkanes 下载免费PDF全文
Teemu Niemi Dr. Jesus E. Perea‐Buceta Dr. Israel Fernández Otto‐Matti Hiltunen Vili Salo Sari Rautiainen Dr. Minna T. Räisänen Prof. Timo Repo 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(30):10355-10359
The multicomponent assembly of pharmaceutically relevant N‐aryl‐oxazolidinones through the direct insertion of carbon dioxide into readily available anilines and dibromoalkanes is described. The addition of catalytic amounts of an organosuperbase such as Barton's base enables this transformation to proceed with high yields and exquisite substrate functional‐group tolerance under ambient CO2 pressure and mild temperature. This report also provides the first proof‐of‐principle for the single‐operation synthesis of elusive seven‐membered ring cyclic urethanes. 相似文献
60.
Hiu Yung Lam Rannveig Ingebrigtsen Gaarden Xuechen Li 《Chemical record (New York, N.Y.)》2014,14(6):1086-1099
Daptomycin, the first antibiotic of its class, provides a new structural motif for the development of new antibiotics. Recently, we have completed the total synthesis of daptomycin. The development of the successful synthetic strategy is described here, including the application of serine/threonine ligation mediated peptide cyclization to the daptomycin macrocyclization. 相似文献