Novel Nucleolipids of Pyrimidine β‐D‐Ribonucleosides: Combinatorial Synthesis, Spectroscopic Characterization, and Cytostatic/Cytotoxic Activities

Abstract

Four series of nucleolipids with either uridine, 5-methyluridine, 5-fluorouridine, and 6-azauridine as β-D-ribonucleoside component have been prepared in a combinatorial (not parallel!) manner (see Formulae). All compounds have been characterized by elemental analyses, ESI mass spectrometry as well as by (1) H-, and (13) C-NMR, and UV spectroscopy. A selection of eight nucleolipids with different lipophilizing moieties, based on earlier findings, as well as of 5-fluorouridine as control were first tested on their cytotoxic effect towards PMA-differentiated human THP-1 macrophages. Those compounds which did not exhibit a significant inhibitory effect on the survival of the macrophages were next tested on their cytostatic/cytotoxic effect towards the human astrocytoma/oligodendroglioma GOS-3 cells as well as against the rat malignant neuroectodermal BT4Ca cell line. Additionally, induction of apoptosis of the cell lines was evaluated. It turned out that particularly a combined lipophilization of the nucleosides by an 2',3'-O-ethyl levulinate residue plus a farnesyl moiety at N(3) of the pyrimidine moiety of the corresponding nucleolipids leads to an active compound with the highest probability.

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

“…We also showed that saponification of the O ‐2′,3′‐ethyl levulinate ketal group yielding an O ‐2′,3′‐levulinate residue at the glyconic moiety of the ribonucleoside abolishes any cancerostatic/cancerotoxic activity toward human cancer cell lines . We extended our study to canonical purine β ‐ d ‐ribonucleoside nucleolipids, particularly to inosine and adenosine derivatives …”

“…Reaction of the pyrimidine β ‐ d ‐ribonucleosides 1Aa – 1Ad and the purine β ‐ d ‐ribonucleosides 1Ba and 1Bb with either heptan‐4‐one or undecan‐6‐one gave after chromatographic work‐up the symmetric O‐2′,3′‐ketals 2Aa – 2Ah and 2Ba – 2Bd ( Scheme 1 ). Some of these nucleolipids had already been prepared before and were now re‐synthesized. For comparison, adenosine was ketalized with cyclopentadecanone yielding the O‐2′,3′‐cyclic cyclopentadecanylidene nucleolipid 4 ( Scheme 2 ).…”

“…The integrity of new compounds as well as their correct structure was proved by elemental analyses, 1 H‐, 13 C‐NMR and UV‐Vis spectroscopy; assignments of 13 C‐NMR resonances was performed by DEPT‐135, as well as by gradient‐selected homo‐ and heteronuclear correlation spectroscopy ( Bruker pulse programs, 1 H, 13 C‐HSQCETGP; 1 H, 1 H‐COSYGPSW). In case of compounds 3Aa – 3Ah and 3Ba and 3Bb , an O(4/6)‐farnesylation was clearly ruled out by measuring pH‐dependent UV spectra …”

“…Recently, we demonstrated that the introduction of either symmetric O ‐2′,3′‐alkylidene ketal groups of medium chain length (C 7 – C 19 ) into a β ‐ d ‐ribonucleoside (type A) or a lipophilization of a nucleoside by an O ‐2′,3′‐ethyllevulinate moiety in combination with a trans,trans ‐farnesyl residue at N(3) (for pyrimidine) or at N(1) (for purines) (type B) leads to nucleolipids with pronounced cancerostatic/cancerotoxic activity towards various cancer cell lines . We also showed that saponification of the O ‐2′,3′‐ethyl levulinate ketal group yielding an O ‐2′,3′‐levulinate residue at the glyconic moiety of the ribonucleoside abolishes any cancerostatic/cancerotoxic activity toward human cancer cell lines .…”

Nucleoside surfaces as a platform for the control of surface hydrophobicity

“…36 Of course, modication of the nucleic base might negate (or at least dramatically decrease) the possible recognition with complementary nucleosides; however, it might allow nucleoside selfassemblies, as observed in nucleolipids. 37,38 As mentioned, the nucleoside and EDOT parts were linked using nucleophilic substitution. It was thus necessary to prepare EDOT bearing a good leaving group (Br).…”