Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)­aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety

Isoquinoline-Based Lanthanide Complexes: Bright NIR Optical Probes and Efficient MRI Agents

In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-infrared emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, <b>L1</b>, <b>L2</b> and <b>L3</b>, have been synthesized and the corresponding Gd³⁺, Nd³⁺ and Yb³⁺ complexes investigated. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biological applications and (ii) are able to emit a sufficient number of photons to ensure sensitive NIR detection for microscopic imaging. Here we report the first observation of a NIR signal arising from a Ln³⁺ complex in aqueous solution in a microscopy setup. The lanthanide complexes have high thermodynamic stability (log <i>K</i>_LnL =17.7–18.7) and good selectivity for lanthanide ions versus the endogenous cations Zn²⁺, Cu²⁺, and Ca²⁺ thus preventing transmetalation. A variable temperature and pressure ¹⁷O NMR study combined with nuclear magnetic relaxation dispersion measurements yielded the microscopic parameters characterizing water exchange and rotation. Bishydration of the lanthanide cation in the complexes, an important advantage to obtain high relaxivity for the Gd³⁺ chelates, has been demonstrated by ¹⁷O chemical shifts for the Gd³⁺ complexes and by luminescence lifetime measurements for the Yb³⁺ analogues. The water exchange on the three Gd³⁺ complexes is considerably faster (<i>k</i>_ex²⁹⁸ = (13.9–15.4) × 10⁶ s^–1) than on commercial Gd³⁺-based contrast agents and proceeds <i>via</i> a dissociative mechanism, as evidenced by the large positive activation volumes for Gd<b>L1</b> and Gd<b>L2</b> (+10.3 ± 0.9 and +10.6 ± 0.9 cm³ mol^–1, respectively). The relaxivity of Gd<b>L1</b> is doubled at 40 MHz and 298 K in fetal bovine serum (<i>r</i>₁ = 16.1 vs 8.5 mM^–1 s^–1 in HEPES buffer), due to hydrophobic interactions between the chelate and serum proteins. The isoquinoline core allows for the optimization of the optical properties of the luminescent lanthanide complexes in comparison to the pyridinic analogues and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biological applications. <b>L2</b> and <b>L3</b> bear two methoxy substituents on the aromatic core in ortho and para positions, respectively, that further modulate their electronic structure. The Nd³⁺ and Yb³⁺ complexes of the ligand <b>L3</b>, which incorporates the <i>p</i>-dimethoxyisoquinoline moiety, can be excited up to 420 nm. This wavelength is shifted over 100 nm toward lower energy in comparison to the pyridine-based analogue. The luminescence quantum yields of the Nd³⁺ (0.013–0.016%) and Yb³⁺ chelates (0.028–0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water molecules. More importantly, the 980 nm NIR emission band of Yb<b>L3</b> was detected with a good sensitivity in a proof of concept microscopy experiment at a concentration of 10 μM in fetal bovine serum. Our results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient number of photons to ensure sensitive detection in practical applications. In particular, these ligands containing an aromatic core with coordinating pyridine nitrogen can be easily modified to tune the optical properties of the NIR luminescent lanthanide complexes while retaining good complex stability and MRI characteristics for the Gd³⁺ analogues. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixture of Gd³⁺ and Yb³⁺/Nd³⁺ complexes using an identical chelator. Given the presence of two inner sphere water molecules, important for MRI applications of the corresponding Gd³⁺ analogues, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln³⁺ ions but also for the design of combined NIR optical and MRI probes

Synthesis of [1,3,4]Thiadiazolo[3′,2′:1,2]imidazo[4,5‑<i>c</i>]quinolines including Pictet–Spengler Reaction and Exploration of Their C‑2 Reactivity through S_NAr

This work reports the design of [1,3,4]­thiadiazolo­[3′,2′:1,2]­imidazo­[4,5-<i>c</i>]­quinolines using a Pictet–Spengler reaction. The scope of the reaction was achieved from 6-(2-aminophenyl)­imidazo­[2,1-<i>b</i>]­[1,3,4]­thiadiazole derivatives and available aldehydes. A wide range of aldehydes were employed to examine the scope of the cyclization. In parallel, a mechanism investigation was realized and showed a hydride transfer which led to a dismutation of the intermediate species. To complete this methodological study, a “sequential” oxidation/S_NAr procedure was performed to achieve C-2 nucleophilic substitution using several amine types

Glycosaminoglycan mimetics obtained by microwave-assisted sulfation of marine bacterium sourced infernan exopolysaccharide

International audienceSulfated glycosaminoglycans (GAGs) are fundamental constituents of both the cell surface and extracellular matrix. By playing a key role in cell-cell and cell-matri x interactions, GAGs are involved in many physiological and pathological processes. To design GAG mimetics with similar therapeutic potential as the natural ones, the specific structural features, among them sulfate content, sulfation pattern, and chain length, should be considered. In the present study, we describe a sulfation method based on microwave radiation to obtain highly sulfated derivatives as GAG mimetics. The starting low-molecular-weight (LMW) derivative was prepared from the infernan exopolysaccharide, a highly branched naturally slightly sulfated heteropolysaccharide synthesized by the deep-sea hydrothermal vent bacterium Alteromonas infernus. LMW highly sulfated infernan derivatives obtained by conventional heating sulfation have already been shown to display GAG-mimetic properties. Here, the potential of microwave-assisted sulfation versus that of the conventional method to obtain GAG mimetics was explored. Structural analysis by NMR revealed that highly sulfated derivatives from the two methods shared similar structural features, emphasizing that microwave-assisted sulfation with a 12-fold shorter reaction time is as efficient as the classical one

PiB-Conjugated, Metal-Based Imaging Probes: Multimodal Approaches for the Visualization of β‑Amyloid Plaques

In an effort toward the visualization of β-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a well-established marker of Aβ plaques, to DO3A-monoamide that is capable of forming stable, noncharged complexes with different trivalent metal ions including Gd³⁺ for MRI and ¹¹¹In³⁺ for SPECT applications. Proton relaxivity measurements evidenced binding of Gd­(DO3A-PiB) to the amyloid peptide Aβ_1–40 and to human serum albumin, resulting in a two- and four-fold relaxivity increase, respectively. Ex vivo immunohistochemical studies showed that the DO3A-PiB complexes selectively target Aβ plaques on Alzheimer’s disease human brain tissue. Ex vivo biodistribution data obtained for the ¹¹¹In-analogue pointed to a moderate blood–brain barrier (BBB) penetration in adult male Swiss mice (without amyloid deposits) with 0.36% ID/g in the cortex at 2 min postinjection

Design, Synthesis, and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/mTOR Dual Inhibitors

The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments