Nucleolipids of the Nucleoside Antibiotics Formycin A and B: Synthesis and Biomedical Characterization particularly using Glioblastoma Cells.

Two lipophilic derivatives of formycin A (1) and formycin B (5) carrying an O-2',3'-ethyllevulinate ketal group have been prepared. These were base-alkylated at N(1) (for 1) and N(1) and N(6) (for 5) with both, isopentenyl or all-trans farnesyl residues. Upon the prenylation side reactions were observed, resulting in the formation of nucleolipids with a novel tricyclic nucleobase (→ 4a,b). In case of formycin B O-2',3'-ethyllevulinate (6) farnesylation gave the double prenylated nucleolipid 7. All new compounds were characterized by 1H-, 13C-, UV-Vis, and fluorescence spectroscopy, by ESI mass spectrometry and/or by elemental analysis.LogP determinations between water and n-octanol as well as water and cyclohexane of a selection of compounds allowed qualitative conclusions concerning their potential blood-brain barrier passage efficiency. All compounds were investigated in vitrowith respect to their cytotoxic activity toward rat malignant neuroectodermal BT4Ca as well as against a series of human glioblastoma cell lines (GOS 3, U-87 MG and GBM 2014/42). In order to differentiate between anticancer and side effects of the novel nucleolipids, we also studied their activity on PMA-differentiated human THP-1 macrophages. Here we show, that particularly the formycin A derivative 3b possesses promising antitumor propertiesin several cancer cell lines with profound cytotoxic effects partly on human glioblastoma cells, with a higher efficacy than the chemotherapeutic drug 5-fluorouridine.