Synthesis and anticancer activities of amphiphilic 5-fluoro-2′-deoxyuridylic acid prodrugs

• Published in: European journal of medicinal chemistry Vol. 40; no. 5; pp. 494 - 504
• Main Authors: Ludwig, Peter S., Schwendener, Reto A., Schott, Herbert
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.05.2005; Elsevier
• Subjects: 5-Fluoro-2′-deoxyuridine derivatives; Amphiphilic heterodinucleoside phosphates; Anticancer prodrugs; Antimetabolites; Antimetabolites, Antineoplastic - chemical synthesis; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Fluorodeoxyuridylate - analogs & derivatives; Fluorodeoxyuridylate - chemical synthesis; Fluorodeoxyuridylate - pharmacology; General aspects; Humans; Life Sciences & Biomedicine; Liponucleotide; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Surface Properties; 5-FdU-5-FdC hex = 5-fluoro-2′-deoxyuridylyl-(3′ → 5′)-5-fluoro-N 4-hexadecyl-2′-deoxycytidine; Amphiphilic heterodinucleoside phosphates; Liponucleotide; of the liponucleotide: Oct 1Gro-(3 → 5′)-5-FdU = 1- O-octadecyl-rac-glycerylyl-(3 → 5′)-5-fluoro-2′-deoxyuridine and of the monomers; ddC pam-(5′ → 5′)-5-FdU(Ac) = N 4-palmitoyl-2′,3′-dideoxycytidylyl-(5′ → 5′)-3′- O-acetyl-5-fluoro-2′-deoxyuridine; p5-FdC oct = 5′-fluoro-N 4-octadecyl-2′-deoxycytidine-5′-monophosphate; 5-FdC hex = 5-fluoro-N 4-hexadecyl-2′-deoxycytidine; 5FdC oct-5FdU = 5-fluoro-N 4-octadecyl-2′-deoxycytidylyl-(3′ → 5′)-5-fluoro-2′-deoxyuridine; Heterodinucleoside phosphates; Anticancer prodrugs; Antimetabolites; 5-Fluoro-2′-deoxyuridine derivatives; anticancer prodruggs; CELLS; DINUCLEOSIDE PHOSPHATE DERIVATIVES; IN-VITRO; VIRUS; antimetabolites; 5-fluoro-2 '-deoxyuridine derivatives; liponucleotide; AZT; amphiphilic heterodinucleoside phosphates; Antineoplastic agent; Dinucleotide; Phospholipid; Cytotoxicity; Liponucleotid; Structure activity relation; Chemical synthesis; Tumor cell; Human; Aliphatic compound; Prodrug; Complex lipid; Deoxyribonucleotide; Amphiphilic compound; In vitro; Cytosine derivatives; Cell line; Antimetabolic; Fluorine Organic compounds; Pyrimidine nucleotide; 5-Fluoro-2'-deoxyuridine derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2004.12.006

Amphiphilic anticancer prodrugs of 5′-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP) were synthesized according to the hydrogen phosphonate method by coupling lipophilic cytosine derivatives or a phospholipid with 5-fluoro-2′-deoxyuridine (5-FdU). Studies within the in vitro Anticancer Screen Program of the National Cancer Institute have demonstrated high anticancer activities of the heterodinucleoside phosphates: N 4-palmitoyl-2′-deoxycytidylyl-(3′ → 5′)-3′- O-acetyl-5-fluoro-2′-deoxyuridine (dC pam-5-FdU(Ac), N 4-palmitoyl-2′,3′-dideoxycytidylyl-(5′ → 5′)-3′- O-acetyl-5-fluoro-2′-deoxyuridine (ddC pam-(5′ → 5′)-5-FdU(Ac), 5-fluoro-2′-deoxyuridylyl-(3′ → 5′)-5-fluoro-N 4-hexadecyl-2′-deoxycytidine (5-FdU-5-FdC hex), and of the new liponucleotide 1- O-octadecyl-rac-glycerylyl-(3 → 5′)-5-fluoro-2′-deoxyuridine (Oct 1Gro-(3 → 5′)-5-FdU). The anticancer activities of these prodrugs are comparable to those of 5-FdU and the tumor specificities are modulated by their structures. The highest cytotoxic activity being even superior to 5-FdU was expressed by the dimer 5-FdU-5-FdC hex.