Nucleolipids of the Nucleoside Antibiotics Formycins A and B: Synthesis and Biomedical Characterization Particularly Using Glioblastoma Cells

Autor(en): Rosemeyer, Helmut 
Knies, Christine
Hammerbacher, Katharina
Bender, Eugenia
Bonaterra, Gabriel A.
Hannen, Ricarda
Bartsch, Joerg W.
Nimsky, Christopher
Kinscherf, Ralf
Stichwörter: Biochemistry & Molecular Biology; Chemistry; Chemistry, Multidisciplinary; COLON; cytotoxicity; drug profiling; formycins A and B; glioblastoma; nucleolipids; PREDICTION; synthesis design
Erscheinungsdatum: 2019
Herausgeber: WILEY-V C H VERLAG GMBH
Journal: CHEMISTRY & BIODIVERSITY
Volumen: 16
Ausgabe: 4
Zusammenfassung: 
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 H-1-, C-13-, 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 invitro 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.
ISSN: 16121872
DOI: 10.1002/cbdv.201900012

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