Werner Löwe

The Ether Lipid Inositol-C2-PAF is a Potent Inhibitor of Cell Proliferation in HaCaT Cells

The search for specific anticancer drugs that do not interfere with DNA synthesis or influence the cytoskeleton has led to the development of modified phospholipids with antiproliferative properties. These compounds cause remodeling of the structure and function of plasma membranes. Recently, we described novel compounds, the glycosidated phospholipids, that surprisingly inhibit cell proliferation. These compounds contain α‐D‐glucose in the sn‐2 position of the glycerol backbone of phosphatidylcholine (PC) and platelet‐activating factor (PAF), which gives rise to 2‐glucophosphatidylcholine (Glc‐PC) and 1‐O‐octadecyl‐2‐O‐α‐d‐glucopyranosyl‐sn‐2‐glycero‐3‐phosphatidylcholine (Glc‐PAF), respectively. Glc‐PC and Glc‐PAF inhibit the growth of HaCaT cells at nontoxic concentrations. Here we report the introduction of myo‐inositol, in place of α‐D‐glucose, in the sn‐2 position of the glycerol backbone; this leads to two diastereomeric 1‐O‐octadecyl‐2‐O‐(2‐(myo‐inositolyl)‐ethyl)‐sn‐glycero‐3‐(R/S)‐phosphatidylcholines (Ino‐C2‐PAF). The inositol‐containing PAF enhances the antiproliferative capacity (IC50=1.8 μM) and reduces the cytotoxicity relative to Glc‐PAF (LC50=15 μM). Through biological assays, we showed that, in HaCaT cells, Ino‐C2‐PAF causes upregulation of the keratinocyte‐specific differentiation marker involucrin, increases the activity of the differentiation marker transglutaminase, and induces apoptosis at nontoxic concentrations. Ino‐C2‐PAF therefore seems to be a promising candidate for development as an antiproliferative drug for the treatment of hyperproliferative diseases of the skin.

Heterocyclic congeners of PD 128,907 with a partially hydrogenated benzomorpholine moiety as potential dopamine D3-receptor ligands

Abstract With a straightforward seven-step synthesis, racemic perhydro[1,4]benzoxazin-6-on was synthesized in overall good yields via regioselective epoxid ring-opening to the corresponding β-aminoalcohol. The oxazine derivative was the key intermediate for the preparation of heteroaromatic analogues of the dopamine D 3 -receptor preferring agonist PD 128,907. The morpholine moiety of PD 128,907 was incorporated in diazole and diazine compounds obtained by different ring closure reactions. The target compounds obtained were structurally related to non-ergot heteroaromatic dopamine agonists which display preferential activity at the D 3 receptor, e.g., quinpirole, quinerolane, or pramipexole. The five membered aminothiazole, aminoselenazole, and pyrazole derivatives showed at least one order of magnitude higher binding at the human D 3 receptor than that at the D 2L receptor. Although the novel compounds displayed K i values only in the micromolar concentration range, the most active ones showed full agonist activity in a functional assay on mitogenesis.