Philippe Maurin

Significant relaxivity gap between a low-spin and a high-spin iron(II) complex of structural similarity: an attractive off–on system for the potential design of responsive MRI probes

We have identified a pair of structurally similar iron complexes in the oxidation state II that exist in a low-spin and a high-spin electronic spin state in aqueous media, respectively. The low-spin, diamagnetic complex (LS, 1) is mute in MRI while the high-spin, paramagnetic complex (HS, 2) generates considerable contrast in MRI. These results demonstrate that iron(II) complexes, hitherto neglected for contrast enhancement in MRI, have potential for the design of an MRI probe that suffers passage from one state to the other under the influence of a targeted biochemical activity and thus operates in an off–on mode. At 300 MHz (proton resonance frequency at 7 T field strength) and in phosphate buffer, we found a longitudinal relaxivity (r1) of 1.29 mM−1 s−1 for 2 that, in light of the difference in unpaired electrons of the central metal atoms (4 for FeII; 7 for GdIII), comes remarkably close to that of gadolinium(III)–DOTA (2.44 mM−1 s−1), a commercialized MRI contrast agent. Since gadolinium complexes are always paramagnetic and can therefore not be muted in MRI, the here presented Fe(II)-based system offers an alternative strategy to develop responsive MRI probes.

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.

Efficient Synthesis of New Steroids Possessing an Aromatic A‐Ring with a 2‐Hydroxy or a 2‐Fluoro Substituent

5-Fluoro-1-iodobenzocyclobutene (7) and 5-tert-butoxy-1-iodobenzocyclobutene (8) have been used for the synthesis of the title compounds. This strategy involves the use of an intramolecular Diels−Alder cycloaddition of o-xylylenes as the key step. We have shown that the introduction of a tert-butyl ether as a protecting group at the beginning of the synthesis, in place of the methyl ether used previously, is a judicious choice by which to obtain steroids possessing an aromatic A-ring with a 2-OH substituent. Finally, the vinyl groups of the synthesized fluoro and hydroxy steroids have been oxidized by the Wacker process in good yields. An X-ray crystal structure of the fluoro steroid 14b, the trans-anti-trans ring configuration of which matches those in natural products, is reported.

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.

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. Seven variants were prepared and tested in cellulo with our HIV-1 fusion-protein technology that result in an eGFP-based fluorescent readout. Three candidates showed inhibition potency above 20μM and toxicity at higher concentrations, making them attractive targets for further refinement. Importantly, our class of original inhibitor candidates is not recognized by two major multidrug resistance pumps, quite in contrast to most clinically applied HIV-1 protease inhibitors.