Synthesis and Biological Evaluation of a Valinomycin Analog Bearing a Pentafluorophenyl Active Ester Moiety

A valuable analog of the K⁺-ionophore valinomycin (<b>1</b>), bearing a pentafluorophenyl ester moiety, has been obtained by selective reaction between the tertiary hydroxyl moiety of analog <b>2</b> (available from valinomycin hydroxylation) and the isocyanate group of pentafluorophenyl <i>N</i>-carbonyl glycinate (<b>3</b>) catalyzed by bis­(<i>N</i>,<i>N</i>-dimethylformamide)­dichlorodioxomolybdenum­(VI). LC-HRMS studies show that analog <b>4</b> undergoes easy derivatization under mild conditions by reaction with OH- and NH₂-containing compounds. Mitochondrial depolarization assays suggest that <b>4</b> acts as a K⁺-ionophore, provided that the glycine carboxyl group is appropriately masked

Synthesis and Characterization of a Platinum(II) Complex Tethered to a Ligand of the Peripheral Benzodiazepine Receptor

A peripheral benzodiazepine receptor (PBR) ligand (TZ6, 5) has been selected as receptor-mediated carrier for antitumor cisplatin-like compounds. Compound 5, containing a thiazole ring in position 2 of the imidazopyridine nucleus, is able to act as a dinitrogen chelate toward platinum. The resulting complex, cis-[PtCl2(5)], that is, compound 8, has been fully characterized by NMR techniques and has been shown to possess affinity and selectivity for the PBR comparable to those of 5 (IC50 of 4.6 and 2.81 nM for 8 and 5, respectively; selectivity indexes for PBR greater than 10 000 for both compounds). Hence, a platinum moiety cross-linking the imidazopyridine and the thiazole aromatic rings does not alter the affinity for PBR. The same cross-linking could be responsible for the tendency of 8 to associate in dimers. The equilibrium between monomer and dimer has been investigated by NMR spectroscopy and the corresponding constant determined

2-Phenyl-imidazo[1,2-<i>a</i>]pyridine Compounds Containing Hydrophilic Groups as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors: Synthesis, Binding Affinity and Electrophysiological Studies

A series of imidazopyridine acetamides were synthesized to evaluate the effects of structural changes at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include the introduction of polar substituents or ionizable functional groups at the 2- and 8-position of the imidazopyridine skeleton. The results suggest that substituents endowed with hydrogen bonding acceptor and/or donor properties in the para position of the phenyl ring lead to high affinity for PBR. In electrophysiological studies, it was found that compounds 9, 12, 13, and 28 markedly enhanced GABA-evoked Cl− currents in Xenopus oocytes expressing α1β2γ2 GABAA receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABAA receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion of neurosteroids

Enhanced Mucoadhesion of Thiolated β‑Cyclodextrin by S‑Protection with 2‑Mercaptoethanesulfonic Acid

This study aimed at designing an S-protected thiolated β-cyclodextrin (β-CD) exhibiting enhanced mucoadhesive properties. The native β-CD was thiolated with phosphorus pentasulfide resulting in a thiolated β-CD (β-CD-SH) and subsequently S-protected with 2-mercaptoethanesulfonate (MESNA) to form β-CD-SS-MESNA. The structure of the novel excipient was confirmed by 1H NMR and Fourier-transform infrared spectroscopy. The sulfhydryl content of β-CD-SH, determined by Ellman’s test, was 2281.00 ± 147 μmol/g, and it was decreased to 45.93 ± 19.40 μmol/g by S-protection. Due to thiolation and S-protection, the viscosity of the mixture of mucus with β-CD-SH and β-CD-SS-MESNA increased 1.8 and 4.1-fold, compared to native β-CD, respectively. The unprotected β-CD-SH diffused to a lesser extent into the mucus than native β-CD, while S-protected β-CD-SS-MESNA showed the highest mucodiffusion among the applied CDs. A 1.5- and 3.0-fold higher cellular uptake of β-CD-SH and β-CD-SS-MESNA, compared to the native one, was established on Caco-2 cell line by flow cytometry, respectively, causing slightly decreased cell viability. On account of the enhanced mucoadhesion, this higher cellular uptake does not affect the application potential of β-CD-SS-MESNA as an oral drug delivery system since the carrier remains in the mucus and does not reach the underlying epithelial layer. According to these results, the S-protection of β-CD-SH with MESNA promotes improved mucodiffusion, strong mucoadhesion, and prolonged mucosal residence time

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-selective ligand, 2-(8-(2-(bis­(pyridin-2-yl)­methyl)­amino)­acetamido)-2-(4-chlorophenyl)<i>H</i>-imidazo­[1,2-<i>a</i>]­pyridin-3-yl)-<i>N</i>,<i>N</i>-dipropylacetamide (<b>CB256</b>), which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker

Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration

Antitumor Potential of Conjugable Valinomycins Bearing Hydroxyl Sites: In Vitro Studies

Following our pioneering studies on the direct and efficient introduction of derivatizable hydroxyl handles into the valinomycin (VLM, <b>1</b>) structure, a K⁺-ionophore with potent antitumor activity, the ensuing conjugable analogues (HyVLMs <b>2</b>, <b>3</b>, and <b>4</b>) have herein been compared to the parent macrocycle for their potential antiproliferative effects on a panel of cancer cell lines, namely, human MCF-7, A2780, and HepG2, as well as rat C6 cells. On the basis of IC₅₀ values, we find that hydroxyl analogues <b>3</b> and <b>4</b> are only moderately less active than <b>1</b>, while analogue <b>2</b> experiences a heavily diminished activity. Cytofluorimetric analyses of MCF-7 cells treated with HyVLMs suggest that the latter depolarize mitochondria, thus retaining the typical VLM behavior. It is likely that C6 cells, for which the exceptionally potent cytotoxicity of VLM has never reported previously, follow the same fate, as evidenced by alteration of mitochondrial morphology upon incubation with each ionophore

Preparation and characterization of NC/MIC-COOH.

Absorption (black line), PL (red line) spectra (A), hydrodynamic diameter distribution by intensity (B) and TEM micrograph with positive staining (D) of NC/MIC-COOH dispersed in PBS at pH 7.4. Schematic sketch of NC/MIC-COOH (C).</p

Evaluation of cellular uptake of NC/MIC-COOH by confocal microscopy.

<p>Confocal differential interface contrast and fluorescence micrographs of fixed astrocytes. Cells images after 1 h of incubation time with NC/MIC-COOH at NC concentration of 0.2 nM. Cell images in the differential interference contrast (Panel A), blue (Panel C) and red (Panel D) detection channel. Overlay of blue and red fluorescence detection channels with (Panel B) and without differential interface contrast (Panel E). Scale bar 25 μm.</p

Effect of organic capped CdSe@ZnS NCs on cell viability of astrocytes.

<p>Confluent astrocytes, plated in 96 well plates, were treated with luminescent organic capped CdSe@ZnS NCs or CHCl₃ at the indicated concentrations. The control (CTRL, A) was obtained from untreated astrocytes in serum-free DMEM. After treatment for 24 h at 37°C, 5% CO₂ the cells were subjected to the cell viability test with MTT as described in Experimental section. Micrographs show representative results of cell morphology observed under phase-contrast microscope (50X magnification) after 24 h of treatment with NCs (C, left panel) or CHCl₃ (C, right panel). The graphs represents the cell viability expressed as percentage of cell survival in comparison with control (CTRL) (B). A dose of NCs or CHCl₃ that determined a cell viability < 60% was considered toxic. Data represent the mean values ± SD of three different experiments performed on different cell populations.</p