Combinatorial Synthesis of New Pyrimidine- and Purine--d-Ribonucleoside Nucleolipids: Their Distribution Between Aqueous and Organic Phases and Their In Vitro Activity Against Human- and Rat Glioblastoma Cells In Vitro

Autor(en): Hammerbacher, Katharina
Goertemaker, Katharina
Knies, Christine
Bender, Eugenia
Bonaterra, Gabriel A.
Rosemeyer, Helmut 
Kinscherf, Ralf
Stichwörter: AREA; Biochemistry & Molecular Biology; BRAIN PENETRATION; Chemistry; Chemistry, Multidisciplinary; COLON; conformation; CYTOSTATIC/CYTOTOXIC ACTIVITIES; DERIVATIVES; drug profiling; glioblastoma; LIPOPHILICITY; nucleolipids; NUCLEOSIDES; POLAR MOLECULAR-SURFACE; PREDICTION; THP-1; URIDINE
Erscheinungsdatum: 2018
Herausgeber: WILEY-V C H VERLAG GMBH
Journal: CHEMISTRY & BIODIVERSITY
Volumen: 15
Ausgabe: 9
Zusammenfassung: 
Two series of nucleolipids, O-2,3-heptanylidene- as well as O-2,3-undecanylidene ketals of six -d-ribonucleosides (type A) and partly N-farnesyl derivatives thereof (type B) were prepared in a combinatorial manner. All novel compounds were characterized by elemental analysis and/or ESI mass spectrometry and by UV-, H-1-, and C-13-NMR spectroscopy. Conformational parameters of the nucleosides and nucleolipids were calculated from various (3)J(H,H), (3)J(H-1,C-13), and (5)J(F,H) coupling constants. For a drug profiling, the parent nucleosides and their lipophilic derivatives were studied with respect to their distribution (log P) between water and n-octanol as well as water and cyclohexane. From these data, qualitative conclusions were drawn concerning their possible blood-brain barrier passage efficiency. Moreover, nucleolipids were characterized by their molecular descriptor amphiphilic ratio (a.r.), which describes the balance between the hydrophilicity of the nucleoside headgroup and the lipophilicity of the lipid tail. All compounds were investigated invitro with respect to their cytostatic/cytotoxic activity toward human glioblastoma (GOS 3) as well as rat malignant neuroectodermal BT4Ca cell lines invitro. In order to differentiate between anticancer and side-effects of the novel nucleolipids, they were also studied on their activity on differentiated human THP-1 macrophages.
ISSN: 16121872
DOI: 10.1002/cbdv.201800173

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