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排序方式: 共有54条查询结果,搜索用时 31 毫秒
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Back Cover: Quadruplex DNA‐Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers (Chem. Eur. J. 7/2016)
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13.
Malcolm S. Cole Michael D. Howe Dr. Joseph A. Buonomo Dr. Sachin Sharma Dr. Elise A. Lamont Scott I. Brody Dr. Neeraj K. Mishra Dr. Yusuke Minato Dr. Joshua M. Thiede Dr. Anthony D. Baughn Dr. Courtney C. Aldrich 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(51):e202200995
Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy. 相似文献
14.
William D. Fiers Greg J. Dodge Yang Li Janet L. Smith Robert A. Fecik Courtney C. Aldrich 《Chemical science》2015,6(8):5027-5033
Polyketide synthase (PKS) β-processing domains are responsible for much of the stereochemical complexity of polyketide natural products. Although the importance of β-processing domains has been well noted and significantly explored, key stereochemical details pertaining to cryptic stereochemistry and the impact of remote stereogenic centers have yet to be fully discerned. To uncover the inner workings of ketoreductases (KR) and dehydratases (DH) from the tylosin pathway a didomain composed of TylDH3-KR3 was recombinantly expressed and interrogated with full-length tetraketide substrates to probe the impact of vicinal and distal stereochemistry. In vitro product isolation analysis revealed the products of the cryptic KR as d-alcohols and of the DH as trans-olefins. Steady-state kinetic analysis of the dehydration reaction demonstrated a strict stereochemical tolerance at the β-position as d-configured substrates were processed more than 100 times more efficiently than l-alcohols. Unexpectedly, the k
cat/K
M values were diminished 14- to 45-fold upon inversion of remote ε- and ζ-stereocenters. This stereochemical discrimination is predicted to be driven by a combination of allylic A1,3 strain that likely disfavors binding of the ε-epimer and a loss of electrostatic interactions with the ζ-epimer. Our results strongly suggest that dehydratases may play a role in refining the stereochemical outcomes of preceding modules through their substrate stereospecificity, honing the configurational purity of the final PKS product. 相似文献
15.
Multifaceted Studies of the DNA Interactions and In Vitro Cytotoxicity of Anticancer Polyaromatic Platinum(II) Complexes
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Benjamin J. Pages Dr. Jennette Sakoff Dr. Jayne Gilbert Prof. Alison Rodger Dr. Nikola P. Chmel Nykola C. Jones Dr. Sharon M. Kelly Dale L. Ang Prof. Janice R. Aldrich‐Wright 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(26):8943-8954
This study reports a detailed biophysical analysis of the DNA binding and cytotoxicity of six platinum complexes (PCs). They are of the type [Pt(PL)(SS‐dach)]Cl2, where PL is a polyaromatic ligand and SS‐dach is 1S,2S‐diaminocyclohexane. The DNA binding of these complexes was investigated using six techniques including ultraviolet and fluorescence spectroscopy, linear dichroism, synchrotron radiation circular dichroism, isothermal titration calorimetry and mass spectrometry. This portfolio of techniques has not been extensively used to study the interactions of such complexes previously; each assay provided unique insight. The in vitro cytotoxicity of these compounds was studied in ten cell lines and compared to the effects of their R,R enantiomers; activity was very high in Du145 and SJ‐G2 cells, with some submicromolar IC50 values. In terms of both DNA affinity and cytotoxicity, complexes of 5,6‐dimethyl‐1,10‐phenanthroline and 2,2′‐bipyridine exhibited the greatest and least activity, respectively, suggesting that there is some correlation between DNA binding and cytotoxicity. 相似文献
16.
Beck BJ Aldrich CC Fecik RA Reynolds KA Sherman DH 《Journal of the American Chemical Society》2003,125(41):12551-12557
The unique ability of the pikromycin (Pik) polyketide synthase to generate 12- and 14-membered ring macrolactones presents an opportunity to explore the fundamental processes underlying polyketide synthesis, specifically the mechanistic details of the chain extension process. We have overexpressed and purified PikAIII (module 5) and PikAIV (module 6) and assessed the ability of these proteins to generate tri- and tetraketide lactone products using N-acetylcysteamine-activated diketides and (14)C-methylmalonyl-CoA as substrates. Comparison of the stereochemical specificities for PikAIII and PikAIV and the reported values for the DEBS modules reveals significant differences between these systems. 相似文献
17.
Keya Zhang Kathryn M. Nelson Karan Bhuripanyo Kimberly D. Grimes Bo Zhao Courtney C. Aldrich Jun Yin 《Chemistry & biology》2013,20(1):92-101
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18.
Shi C Geders TW Park SW Wilson DJ Boshoff HI Abayomi O Barry CE Schnappinger D Finzel BC Aldrich CC 《Journal of the American Chemical Society》2011,133(45):18194-18201
BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 ? resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action. 相似文献
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A new effective interaction potential between an electron and a hole of a Mott-Wannier exciton in a polarizable medium is derived following a procedure similar to that of Haken. The variational polaron wave functions used are those first proposed by Haga. Using this effective interaction potential the values of the binding energy of an exciton are calculated variationally in several polar crystals. The values thus obtained agree very well with those derived from experimental measurements and are always considerably smaller than those calculated using Haken's potential. 相似文献