Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
Chemistry ; 24(5): 1062-1066, 2018 Jan 24.
Article in English | MEDLINE | ID: mdl-29168907

ABSTRACT

Photoregulation is among the most promising tools for development of dynamic DNA nanosystems, due to its high spatiotemporal precision, biocompatibility, and ease of use. So far, azobenzene and its derivatives have shown high potential in photocontrolling DNA duplex hybridization by light-dependent photoisomerization. Despite many recent advances, obtaining sufficiently high photoswitching efficiency under conditions more suitable for work with DNA nanostructures are challenging. Here we introduce a pair of arylazopyrazoles as new photoswitches for efficient and reversible control of DNA hybridization achieved even at room temperature with a low number of required modifications. Their photophysical properties in the native state and in DNA strands result in near-quantitative isomerization rates by irradiation with UV and orange light. To demonstrate the applicability of these photoswitches, we have successfully applied one of them to open and close a DNA hairpin by light at room temperature.


Subject(s)
DNA/chemistry , Nanostructures/chemistry , Photochemical Processes , Pyrazoles/chemistry , Chromatography, High Pressure Liquid/methods , Isomerism , Kinetics , Light , Nanotechnology/methods , Temperature
2.
Angew Chem Int Ed Engl ; 56(29): 8417-8421, 2017 07 10.
Article in English | MEDLINE | ID: mdl-28628261

ABSTRACT

The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof-of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Spin Labels , Electron Spin Resonance Spectroscopy , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Humans , Models, Molecular , Molecular Structure , Protein Conformation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Solutions , Structure-Activity Relationship
3.
Antimicrob Agents Chemother ; 59(1): 654-8, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25313210

ABSTRACT

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 µM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates.


Subject(s)
Antimalarials/pharmacology , Benzimidazoles/pharmacology , Plasmodium falciparum/drug effects , Porphobilinogen Synthase/antagonists & inhibitors , Benzimidazoles/chemistry , Humans , Inhibitory Concentration 50 , Plasmodium berghei/drug effects , Plasmodium falciparum/physiology , Thiophenes/chemistry , Thiophenes/pharmacology , Toxoplasma/drug effects
4.
J Med Chem ; 57(6): 2498-510, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24568185

ABSTRACT

The heme biosynthesis enzyme porphobilinogen synthase (PBGS) is a potential drug target in several human pathogens. wALADin1 benzimidazoles have emerged as species-selective PBGS inhibitors against Wolbachia endobacteria of filarial worms. In the present study, we have systematically tested wALADins against PBGS orthologs from bacteria, protozoa, metazoa, and plants to elucidate the inhibitory spectrum. However, the effect of wALADin1 on different PBGS orthologs was not limited to inhibition: several orthologs were stimulated by wALADin1; others remained unaffected. We demonstrate that wALADins allosterically modulate the PBGS homooligomeric equilibrium with inhibition mediated by favoring low-activity oligomers, while 5-aminolevulinic acid, Mg(2+), or K(+) stabilized high-activity oligomers. Pseudomonas aeruginosa PBGS could be inhibited or stimulated by wALADin1 depending on these factors and pH. We have defined the wALADin chemotypes responsible for either inhibition or stimulation, facilitating the design of tailored PBGS modulators for potential application as antimicrobial agents, herbicides, or drugs for porphyric disorders.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Porphobilinogen Synthase/antagonists & inhibitors , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Chlamydia/drug effects , Herbicides/chemical synthesis , Herbicides/pharmacology , Humans , Hydrogen-Ion Concentration , Microbial Sensitivity Tests , Molecular Weight , Pisum sativum , Plants , Porphyrias/drug therapy , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Rickettsia/drug effects , Stereoisomerism , Structure-Activity Relationship , Wolbachia/drug effects
6.
Chem Biol ; 20(2): 177-87, 2013 Feb 21.
Article in English | MEDLINE | ID: mdl-23438747

ABSTRACT

Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.


Subject(s)
Antiprotozoal Agents/pharmacology , Benzimidazoles/pharmacology , Filarioidea/drug effects , Heme/biosynthesis , Thiophenes/pharmacology , Wolbachia/metabolism , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Benzimidazoles/chemistry , Benzimidazoles/therapeutic use , Drug Design , Elephantiasis, Filarial/drug therapy , High-Throughput Screening Assays , Humans , Kinetics , Magnesium/chemistry , Magnesium/metabolism , Porphobilinogen Synthase/antagonists & inhibitors , Porphobilinogen Synthase/metabolism , Symbiosis , Thiophenes/chemistry , Thiophenes/therapeutic use , Wolbachia/enzymology
7.
PLoS One ; 7(7): e41179, 2012.
Article in English | MEDLINE | ID: mdl-22815959

ABSTRACT

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI treatment. Here, we show that the proliferation of the gefitinib-resistant NSCLC cell lines H460 and A549 is reduced by the small molecule SecinH3 which indirectly attenuates EGFR activation by inhibition of cytohesins, a class of recently discovered cytoplasmic EGFR activators. SecinH3 and gefitinib showed a synergistic antiproliferative effect, which correlated with a profound inhibition of Akt activation and survivin expression. Treating mice bearing H460 xenografts with SecinH3 showed the antiproliferative and pro-apoptotic effect of SecinH3 in vivo. Our data suggest that targeting the EGFR indirectly by inhibiting its cytoplasmic activators, the cytohesins, has the potential to improve the treatment of primarily EGFR-TKI resistant lung cancers.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Guanine Nucleotide Exchange Factors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Quinazolines/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation , Cytoplasm/metabolism , Drug Screening Assays, Antitumor/methods , ErbB Receptors/metabolism , Gefitinib , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Nude , Neoplasm Transplantation , Receptor, IGF Type 1/metabolism , Signal Transduction , Triazoles/pharmacology
8.
Chem Commun (Camb) ; 48(9): 1272-4, 2012 Jan 30.
Article in English | MEDLINE | ID: mdl-22179571

ABSTRACT

The synthesis of a trifluoromethylphenyl diazirine photoaffinity probe of the cytohesin inhibitor SecinH3 is described. The probe exhibits improved labelling efficiency over a benzophenone-based probe and thus is more suitable for photoaffinity labelling in complex biological samples.


Subject(s)
Azirines/chemistry , Photoaffinity Labels/chemistry , Triazoles/chemistry , Azirines/chemical synthesis , GTPase-Activating Proteins/analysis , HEK293 Cells , Humans , Photoaffinity Labels/chemical synthesis , Triazoles/chemical synthesis
9.
Phys Chem Chem Phys ; 12(39): 12556-61, 2010 Oct 21.
Article in English | MEDLINE | ID: mdl-20721378

ABSTRACT

The first experiments on trapped rotaxanes are presented, combining collision induced fragmentation and in-trap laser spectroscopy. The intrinsic optical properties of three rotaxanes and their non-interlocked building blocks (thread and macrocycle) isolated in a quadrupolar ion trap are investigated. The excitation and relaxation processes under thermal activation as well as under photo-activation are addressed. The light and collision induced fragmentation pathways show that the degradation mechanisms occurring in the rotaxane are highly dependent on the nature of the thread. In the prospective of operating photoswitchable molecules, photo-activation is achieved in a controlled way by depositing photo-energy in the desired sub-unit of a mechanically interlocked structure.

11.
Nat Nanotechnol ; 5(6): 436-42, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20400967

ABSTRACT

Mechanically interlocked molecules such as rotaxanes and catenanes have potential as components of molecular machinery. Rotaxanes consist of a dumb-bell-shaped molecule encircled by a macrocycle that can move unhindered along the axle, trapped by bulky stoppers. Previously, rotaxanes have been made from a variety of molecules, but not from DNA. Here, we report the design, assembly and characterization of rotaxanes in which both the dumb-bell-shaped molecule and the macrocycle are made of double-stranded DNA, and in which the axle of the dumb-bell is threaded through the macrocycle by base pairing. The assembly involves the formation of pseudorotaxanes, in which the macrocycle and the axle are locked together by hybridization. Ligation of stopper modules to the axle leads to the characteristic dumb-bell topology. When an oligonucleotide is added to release the macrocycle from the axle, the pseudorotaxanes are either converted to mechanically stable rotaxanes, or they disassemble by means of a slippage mechanism to yield a dumb-bell and a free macrocycle. Our DNA rotaxanes allow the fields of mechanically interlocked molecules and DNA nanotechnology to be combined, thus opening new possibilities for research into molecular machines and synthetic biology.


Subject(s)
DNA/chemistry , Models, Molecular , Rotaxanes , Drug Stability , Electrophoresis, Agar Gel , Microscopy, Atomic Force , Nanoparticles/chemistry , Nanoparticles/ultrastructure , Rotaxanes/chemical synthesis , Rotaxanes/chemistry
12.
J Am Chem Soc ; 131(36): 12902-3, 2009 Sep 16.
Article in English | MEDLINE | ID: mdl-19705842

ABSTRACT

Ultrahigh-resolution spectroscopic studies have been performed to elucidate the conformational landscape of the succinamide-based thread 1 that is frequently employed in mechanically interlocked molecular assemblies. We show how dissolving single molecules into a helium nanodroplet enables us to resolve the broad absorption spectrum--which is normally observed--into the separate contributions of individual conformers that are populated under the employed experimental conditions. Excellent agreement is obtained with the results of molecular dynamics calculations. The absorption spectrum of each conformer reveals a splitting of the zero-phonon resonance that is different for each conformer and could thus serve as a spectral signature.

13.
J Am Chem Soc ; 131(7): 2428-9, 2009 Feb 25.
Article in English | MEDLINE | ID: mdl-19199633

ABSTRACT

We report the results of high-resolution spectroscopic studies on isolated, jet-cooled [2]rotaxanes. Employing IR absorption spectroscopy, we show how these noncovalently bound, multicomponent molecular systems that so far have been out of reach from high-resolution techniques, can now be characterized at an unprecedented level. IR absorption spectra of prototypical hydrogen-bond assembled rotaxanes as well as their associated threads and macrocycles are shown to provide a direct view on the effects of interlocking the macrocycle and thread, and to offer a straightforward approach for the study of their structural and dynamical properties.

15.
Proc Natl Acad Sci U S A ; 102(38): 13378-82, 2005 Sep 20.
Article in English | MEDLINE | ID: mdl-16150716

ABSTRACT

Femtosecond 2D-IR spectroscopy has been used to study the structure of a [2]rotaxane composed of a benzylic amide macrocycle that is mechanically interlocked onto a succinamide-based thread. Both the macrocycle and the thread contain carbonyl groups, and by determining the coupling between the stretching modes of these groups from the cross-peaks in the 2D-IR spectrum, the structure of the macrocycle-thread system has been probed. Our results demonstrate that 2D-IR spectroscopy can be used to observe structural changes in molecular devices on a picosecond time scale.


Subject(s)
Rotaxanes/chemistry , Amides/chemistry , Hydrogen Bonding , Molecular Structure , Spectrophotometry, Infrared/methods , Succinates
17.
Org Lett ; 5(11): 1907-10, 2003 May 29.
Article in English | MEDLINE | ID: mdl-12762683

ABSTRACT

[reaction: see text] Peptide [2]- and [3]rotaxanes are assembled in high yields under thermodynamic control using hydrogen bonding interactions and reversible cross olefin metathesis.

SELECTION OF CITATIONS
SEARCH DETAIL
...