Transition metal-catalysed A-ring C-H activations and C(sp2)-C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties.

Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13α-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki-Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13α-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C-H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13α-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.

Formulation and investigation of differently charged ß-cyclodextrin-based meloxicam potassium containing nasal powders.

Nasal systemic drug delivery may provide an easy way to substitute parenteral or oral dosing, however, the excipients have an important role in nasal formulations to increase the permeability of the mucosa and prolong the residence time of the drug. In this work, we aimed to produce meloxicam potassium monohydrate (MXP) containing nasal powders by a nano spray drier with the use of a neutral, an anionic and a cationic ß-cyclodextrin as permeation enhancers, and (polyvinyl)alcohol (PVA) as a water soluble polymer. The following examinations were performed in order to study the effect of the applied excipients on the nasal applicability of the formulations: laser scattering, scanning electron microscope measurement, XRPD, DSC and FTIR measurements, adhesivity, in vitro drug release and permeability tests through an artificial membrane and RPMI 2650 cells. Based on our results, spherical particles were prepared with a size of 1.89-2.21 µm in which MXP was present in an amorphous state. Secondary interactions were formed between the excipients and the drug. The charged cyclodextrin-based formulations showed significantly higher adhesive force values regardless of the presence of PVA. The drug release was fast and complete. The passive diffusion of MXP was influenced not only by the charge of the cyclodextrin, but the presence of PVA, too. The permeation of the drug was enhanced in the presence of the anionic cyclodextrin testing it on RPMI 2650 cell model.