Unprecedented Relaxivity Gap in pH-Responsive Fe -Based MRI Probes.

Two mononuclear ferric complexes are reported that respond to a pH change with a 27- and 71-fold jump, respectively, in their capacity to accelerate the longitudinal relaxation rate of water-hydrogen nuclei, and this starting from a negligible base value of only 0.06. This unprecedented performance bodes well for tackling the sensitivity issues hampering the development of Molecular MRI.

Multiple Sulfonation of Picolyl-Based Complexes Rendering Them Highly Water-Compatible.

Multidentate ligands chosen for the complexation of hard metals frequently exhibit negative charges, which consequently elicits Coulombic compensation of the metal-ion charge. However, ligands favored by soft metal ions are neutral, which prevents the chemist from obtaining electroneutral complexes, let alone ones with a negative total charge. Here, we report on an efficient synthetic method to decorate picolyl-displaying coordination compounds with multiple sulfonate units at their periphery.

Development of Fluorogenic Probes for Rapid High-Contrast Imaging of Transient Nuclear Localization of Sirtuin 3.

Protein labeling using fluorogenic probes enables the facile visualization of proteins of interest. Herein, we report new fluorogenic probes consisting of a rationally designed coumarin ligand for the live-cell fluorogenic labeling of the photoactive yellow protein (PYP)-tag. On the basis of the photochemical mechanisms of coumarin and the probe-tag interactions, we introduced a hydroxy group into an environment-sensitive coumarin ligand to modulate its spectroscopic properties and increase the labeling reaction rate.

In Situ Localization of Enzyme Activity in Live Cells by a Molecular Probe Releasing a Precipitating Fluorochrome.

Current enzyme-responsive, fluorogenic probes fail to provide in situ information because the released fluorophores tend to diffuse away from the reaction sites. The problem of diffusive signal dilution can be addressed by designing a probe that upon enzyme conversion releases a fluorophore that precipitates. An excited-state intramolecular proton transfer (ESIPT)-based solid-state fluorophore HTPQ was developed that is strictly insoluble in water and emits intense fluorescence in the solid state, with λ =410/550 nm, thus making it far better suited to use with a commercial confocal microscope.

Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen.

The origin of ancient ligand/receptor couples is often analyzed via reconstruction of ancient receptors and, when ligands are products of metabolic pathways, they are not supposed to evolve. However, because metabolic pathways are inherited by descent with modification, their structure can be compared using cladistic analysis. Using this approach, we studied the evolution of steroid hormones.

Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death.

Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introduce the photostatins, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics.

"Double gating"--a concept for enzyme-responsive imaging probes aiming at high tissue specificity.

A new archetype of activatable imaging probe is described that responds in an off-on mode with a fluorescent signal only after being consecutively converted by two different enzymes. Pre-pro-proteins are a well-established concept employed by Nature, but "pre-pro-fluorescent" molecular probes have been unknown until now, even though they promise to furnish precious extra information and added specificity over habitual probe technologies. Our prototype probe discriminates cells that express both active β-d-galactosidase and leucine amino-peptidase from those which lack one of these enzymes thanks to the release of a precipitating fluorescent tag.

Tagging live cells that express specific peptidase activity with solid-state fluorescence.

A three-component probe harnesses the extraordinary properties of a solid-state fluorophore for the detection of living cells exhibiting a particular peptidase activity. The off-on mode by which the probe operates, the bright fluorescence of the resulting precipitate, and the rapid response allow an exceptional signal-to-background ratio during microscopic imaging. A tertiary carbamate link between the spacer and phenolic fluorophore is at the heart of the probe's long-term stability.

Magnetogenesis in water induced by a chemical analyte.

This Minireview aims to shed light on the emergent field of inducing a change in the magnetic properties of a solution-phase sample by exposing it to a chemical analyte. A considerable body of knowledge exists on materials that alter their magnetic characteristics after a change in the surrounding physical conditions and a number of cases even exist of solution-phase samples that do so under these same circumstances. However, examples of dissolved molecules or particles that react in this fashion under constant conditions and in response to an analyte are limited.

Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease.

Non-peptidomimetic drug-like protease inhibitors have potential for circumventing drug resistance. We developed a much-improved synthetic route to our previously reported inhibitor candidate displaying an unusual quaternized hemi-aminal. This functional group forms from a linear precursor upon passage into physiological media.

Bispidine platform grants full control over magnetic state of ferrous chelates in water.

A bicyclic ligand platform for iron(II), which allows total control over the complex's magnetic properties in aqueous solution simply by varying one of the six coordination sites of the bispidine ligand, is reported. To achieve this, an efficient synthetic route to an N5 bispidine framework (ligand L4) that features an unsubstituted N-7 site is established. Then, by choosing appropriate N-7-coordinating substituents, the spin state of choice can be imposed on the corresponding ferrous complexes under environmentally relevant conditions in water and near-room temperature.

Magnetogenesis under physiological conditions with probes that report on (bio-)chemical stimuli.

Switched on: A molecular concept allows the generation of magnetism in an aqueous sample under the influence of a freshly added (bio-)chemical analyte. The analyte (a chemical reagent or enzyme) triggers the conversion of the probe, a diamagnetic chelate compound, into a paramagnetic compound (see scheme). The two probes prepared are easily accessible iron(II) chelates, and are operative at physiological conditions and/or in serum.

A robust, high-sensitivity stealth probe for peptidases.

A robust, modular fluorogenic probe system has been developed which allows the highly sensitive off-ON detection of aminopeptidase activity by releasing an exceptionally photostable, insoluble, phenolic ESIPT fluorophore. The probes generate no false positive signal in over 24 hours, but when activated give a signal within 10 minutes.

Awakening of a ferrous complex's electronic spin in an aqueous solution induced by a chemical stimulus.

A low-spin, macrocyclic iron(II) complex in an aqueous solution responds to the addition of a chemical reactant (dithionite) by transformation into a high-spin complex, detectable by measurement of the longitudinal relaxation time (T(1)) of surrounding water hydrogen nuclear spins. The initial compound does not modify T(1) of pure water at concentrations as high as 4 mM. The response is pH-dependent, and the complex is robust at a variety of conditions.

An electroneutral macrocyclic iron(II) complex that enhances MRI contrast in vivo.

The first example of a macrocyclic ferrous complex, where two tetrazolyl pendent arms compensate the charge of the metal center, is synthesized and examined for its capacity to enhance MRI contrast in vitro and in vivo in the mouse.

On the inhibition of HIV-1 protease by hydrazino-ureas displaying the N-->C=O interaction.

To create novel HIV-1 protease (HIV PR) inhibitors, we have extended our investigations of the N-->C=O interaction as a moiety that reproduces electrostatic properties of the transition state of peptidolysis. Consequently, we prepared a series of compounds with an unusual hydrazino-urea core. In polar protic media, these adopt solely a cyclic constitution displaying the interaction on one side of the molecule while offering a urea moiety on the opposite side meant to hydrogen-bond with the enzyme flaps.

Diversity-oriented synthesis of a drug-like system displaying the distinctive N-->C=O interaction.

This study describes the syntheses and characterization of two hydrazino ureas. These fold into a six-membered ring by virtue of the infrequently observed (delta+)N-->C=O (delta-) interaction when solvated by polar protic media. The highly polar functional group resulting from this interaction is hypothesized to especially reproduce electronic but also steric features of the transition states of peptide hydrolysis.

Trimerization products of trifluoroacetone: critical solvent effect on position and kinetics of anomeric equilibria.

In the presence of bases, trifluoroacetone is known to trimerize leading to configurationally labile 6-methyl-2,4,6-tris(trifluoromethyl)tetrahydro-2H-pyran-2,4-diols 1a,b and 2a,b, structurally close to fluorinated carbohydrates. We report herein a complete study of their behavior in solution. The remarkable solvent effect on the two equilibria (1a <--> 1b; 2a <--> 2b) was rationalized using solvent basicity measures and polarity scales.

3,5,7-Tripropyl-1-aza-adamantane-4,6,10-triol.

The title compound, C(18)H(33)NO(3), was prepared according to a highly diastereoselective hydrogenation procedure from 3,5,7-triallyl-1-aza-adamantane-4,6,10-trione. The crystal structure of the title compound contains two crystallographically independent mol-ecules (Z' = 2), which are linked by inter-molecular hydrogen bonding into chains. In contrast to the aza-adamantanones, the aza-adamantanetriol core of the title compound does not show any particular C-C bond elongation.

Fast screening of paramagnetic molecules in zebrafish embryos by MRI.

Zebrafish embryo is a well-established model used in many fields of modern experimental biology. We demonstrate that it provides a promising model platform for exploring fundamental MR aspects that can be used to screen and study active MR molecules before progressing to more complex living systems. Setting up a dedicated MRI methodology, we arrayed a large number of living embryos, which were microinjected at very early stages of development with different contrast agents.

An unusual functional group interaction and its potential to reproduce steric and electrostatic features of the transition states of peptidolysis.

The donor-acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloids, was deliberately established in a peptidomimetic (1a-c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds 1a-c show preferential adoption in methanol and water of a 'folded' conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer.

Polyene substrates with unusual methylation patterns to probe the active sites of three catalytic antibodies.

The synthesis of two tetraenes that differ in their methylation pattern from the natural substrate in lanosterol biosynthesis, 2,3-oxidosqualene, and their examination with three catalytic antibodies is described. The design of these novel, linear terpenoid structures was governed by initial results obtained from the characterization of the three catalytic antibodies. These were generated by immunization with a steroidal hapten that mimics multicyclization without the necessity for anti-Markovnikov additions or ring expansions.

Convergence of Catalytic Antibody and Terpene Cyclase Mechanisms: Polyene Cyclization Directed by Carbocation-π Interactions.

A tandem cationic cyclization cascade similar to a terpenoid cyclase reaction is catalyzed by antibody HA5-19A4. The 2.7-Å resolution crystal structure of the Fab-hapten complex reveals convergence with the same catalytic strategy employed by a terpenoid cyclase: both serve as templates that enforce the productive conformation of a flexible polyene substrate, and both stabilize carbocation intermediates through cation-π interactions with multiple aromatic residues in their active sites.