Nucleolipids of the Nucleoside Antibiotics Formycins A and B: Synthesis and Biomedical Characterization Particularly Using Glioblastoma Cells. Issue 4 (2nd April 2019) - Rosemeyer, Helmut
Abstract: Two lipophilic derivatives of formycin A (1 ) and formycin B (5 ) carrying an O ‐2′, 3′‐(ethyl levulinate) 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 and all‐ trans ‐farnesyl residues. Upon the prenylation, side reactions were observed, resulting in the formation of nucleolipids with a novel tricyclic nucleobase (→4a, 4b ). In the case of formycin B, O ‐2′, 3′‐(ethyl levulinate) (6 ) farnesylation gave the double prenylated nucleolipid 7 . All new compounds were characterized by 1 H‐, 13 C‐, UV/VIS and fluorescence spectroscopy, by ESI‐MS spectrometry and/or by elemental analysis. Log P determinations between water and 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 vitro with 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 properties in several cancer cell lines with profound cytotoxic effects partly on human glioblastoma cells, with a higher efficacy than the chemotherapeutic drug 5‐fluorouridine. Abstract :