Pyridazinone derivatives as potential anti-inflammatory agents: synthesis and biological evaluation as PDE4 inhibitors.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), which controls the intracellular level of cyclic adenosine monophosphate (cAMP), has aroused scientific attention as a suitable target for anti-inflammatory therapy of respiratory diseases. This work describes the development and characterization of pyridazinone derivatives bearing an indole moiety as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4-(5-methoxy-1H-indol-3-yl)-6-methylpyridazin-3(2H)-one possesses promising activity, and selectivity towards PDE4B isoenzymes and is able to regulate potent pro-inflammatory cytokine and chemokine production by human primary macrophages.

Novel approach to accurately predict bond strength and ligand lability in platinum-based anticancer drugs.

Prompted by the antineoplastic properties of cisplatin, a plethora of platinum(ii)-based complexes have been synthesized in the past decades. At present, their rational design is based on a number of structure-activity relationships involving the nature of the ligands initially coordinated to platinum(ii): either non-labile (acting as a carrier) or labile (undergoing substitution). The coordinate bond strength of the labile ligand plays a key role in the first step of the drug mechanism of action, i.e., the hydrolysis process, which is associated to the retention time of the medicine in the body. Therefore, an accurate determination of the metal-ligand bond strength becomes highly relevant as it will help the rational design of novel chemotherapeutic agents. Herein, we challenge the recently developed intrinsic bond strength index (IBSI) as a rapid and practical tool to assess the ligand lability in Pt(ii) complexes. In a first stage, given the importance of the trans-effect in synthetic strategies of cisplatin-based drugs, the effect of eleven trans-directing ligands T is quantified in two sets of complexes [Pt(NH3)2(H2O)T]n+ and [PtCl2(NH3)T]m+ where T = H2O, F-, NH3, Cl-, Br-, I-, SO32-, CH3-, CN-, CO, and H-. An essential outcome of this work is a novel index IBSItrans = IBSIσ + IBSIπ able to rank the directing ligands by their trans-effect according to their σ-donation and π-backbonding electronic contributions. In a second stage, we apply the IBSI score to a panel of eleven case studies, comprising mostly antineoplastic agents, such as cisplatin, carboplatin, lobaplatin etc., in order to quantify the coordinate bond strength of the ligands, providing insights about the hydrolysis process. The obtained results, in good agreement with experimental data and reported theoretical studies, demonstrate that the IBSI score is able to deliver a rapid and reliable picture of the coordinate bond strength, representing a chemically intuitive tool helpful for the development of novel anticancer agents prior to synthetic efforts.

Design of a multifunctionalizable BODIPY platform for the facile elaboration of a large series of gold(i)-based optical theranostics.

A simple trifunctional BODIPY platform was designed. The high potential of this platform was validated via the elaboration of twelve optical theranostics. More specifically, we reported on the synthesis, the characterization, the photophysical properties, and the evaluation of the hydrophilicity properties of the different BODIPY derivatives, as well as a theoretical rationalization of the intriguing chemical behavior of some of them. The antiproliferative evaluation and confocal imaging of the different compounds in three human and murine cancer cell lines were performed and analysed, along with the measurement of gold(i) uptake in one cancer cell line via ICP-MS.

Boron Difluoride Curcuminoid Fluorophores with Enhanced Two-Photon Excited Fluorescence Emission and Versatile Living-Cell Imaging Properties.

The synthesis of boron difluoride complexes of a series of curcuminoid derivatives containing various donor end groups is described. Time-dependent (TD)-DFT calculations confirm the charge-transfer character of the second lowest-energy transition band and ascribe the lowest energy band to a "cyanine-like" transition. Photophysical studies reveal that tuning the donor strength of the end groups allows covering a broad spectral range, from the visible to the NIR region, of the UV-visible absorption and fluorescence spectra. Two-photon-excited fluorescence and Z-scan techniques prove that an increase in the donor strength or in the rigidity of the backbone results in a considerable increase in the two-photon cross section, reaching 5000 GM, with predominant two-photon absorption from the S0-S2 charge-transfer transition. Direct comparisons with the hemicurcuminoid derivatives show that the two-photon active band for the curcuminoid derivatives has the same intramolecular charge-transfer character and therefore arises from a dipolar structure. Overall, this structure-relationship study allows the optimization of the two-photon brightness (i.e., 400-900 GM) with one dye that emits in the NIR region of the spectrum. In addition, these dyes demonstrate high intracellular uptake efficiency in Cos7 cells with emission in the visible region, which is further improved by using porous silica nanoparticles as dye vehicles for the imaging of two mammalian carcinoma cells type based on NIR fluorescence emission.