Adenosine and 1,N6-Ethenoadenosine-Derived Nucleolipids: Synthesis, Lipophilicity (logP), and Cytotoxic Activity Compared to Conventional Cytostatics in Glioma and Glioblastoma Cell Lines

A series of nucleolipid derivatives based on adenosine and 1,N6-ethenoadenosine was synthesized, and their cytotoxicity was evaluated in glioma and glioblastoma cell models. Twenty O-2′,3′-ketalized nucleolipid derivatives were prepared as symmetric and asymmetric adenosine analogs. The lipophilicity was determined using the octanol/water partition method, yielding logPOW values from −0.04 to 4.08. First, cytotoxicity was screened in rat/human glioma cell lines (BT4Ca/GOS-3) using a PrestoBlue™ viability assay, with 5-fluorouridine (5-FUrd) as the reference compound. Selected derivatives with the highest cytotoxicity were evaluated in human glioblastoma cell lines U87 and U251, and their efficacy was compared with the chemotherapeutic agent temozolomide (TMZ). PMA-differentiated human THP-1 macrophages were used to assess cytotoxic side effects in human immune-related cells. Several derivatives induced 90–100% cytotoxicity at 50 µM after 48 h, with cytotoxicity increasing with alkyl chain length and reaching a maximum for derivatives bearing medium-length chains (C15–C17). In contrast, shorter or longer chains caused reduced activity. Cytotoxicity was independent of symmetric or asymmetric ketal configuration, while 1,N6-ethenoadenosine ketal derivatives displayed higher activity than the corresponding adenosine ketals. These novel derivatives indicate that lipophilicity and alkyl chain length are responsible for the cytotoxic effect in glioma and glioblastoma, and that they are more effective than 5-FUrd and TMZ.