Barbara Garofalo

Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2s ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.

Chiral HPLC Resolution of the Wieland–Miescher Ketone and Derivatives

Abstract The direct HPLC resolution of four structurally related compounds, the Wieland‐Miescher ketone, its C(5) homologue, and their C(1) dioxolane derivatives, was studied on commercially available polysaccharide‐based chiral stationary phases (CSPs) cellulose tris‐(3,5‐dimethylphenylcarbamate) (Chiralcel OD‐H), native β‐cyclodextrin (Cyclobond I), and acetylated, carboxymethylated and permethylated β‐cyclodextrins. The retention, resolution, and elution sequence of the enantiomeric couples were compared using different mobile phases. Baseline enantioseparation of all examined compounds was achieved only on the carboxymethyl‐derivatized β‐cyclodextrin stationary phase that appeared the most effective chiral selector for this class of compounds. Native, acetylated‐, and permethylated‐β‐cyclodextrin CSPs exhibited specific selectivity providing, in general, partial resolution of the compounds under investigation. On Chiralcel OD‐H, only two enantiomeric couples were fully separated. Elution orders depended on CSPs. To optimize chiral separation conditions, the influence of mobile phase composition on column retention and selectivity was also investigated.

A Novel Multi-step Virtual Screening for the Identification of Human and Mouse mPGES-1 Inhibitors.

We present here the development of a novel virtual screening protocol combining Structure‐based and Ligand‐based drug design approaches for the identification of mouse mPGES‐1 inhibitors. We used the existing 3D structural data of the murine enzyme to hypothesize the inhibitors binding mode, which was the starting point for docking simulations, shape screening, and pharmacophore hypothesis screening. The protocol allowed the identification of 16 mouse mPGES‐1 inhibitors with low micromolar activity, which, notably, also inhibit the human enzyme in the same concentration range. The inhibitors predicted binding mode is expected to be the base for the rational drug design of new potent dual species inhibitors of human and murine mPGES‐1.