title: Structure-activity relationships of cytotoxic cholesterol-modified DNA duplexes.
abstract: Short DNA duplexes with cholesterol linked at the 3'-terminus of each strand have unique, selective cytotoxic properties. The structural requirements for biological activity were explored through chemical synthesis of analogs and testing in cultured hepatoma cells. Effects of modifications to the sequence, backbone, 3'-sterol, 3'-linker, and 5'-terminus were evaluated. Self-complementary 3'-modified oligodeoxynucleotide (ODN) 10-mers were prepared from solid supports bearing the modification and linker of interest. Any changes to the normal phosphodiester backbone were poorly tolerated. The presence of cholesterol or a closely related sterol was an absolute requirement for activity. The length and position of attachment of the linker to cholesterol was important, with longer linkers showing reduced activity. Large, lipophilic groups at the 5'-terminus gave reduced cytotoxicity and poor solubility properties. The short length and unique structure of these ODNs allowed efficient automated synthesis on a 400 mumol scale and simplified purification.
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002999:Clone Cells; D004247:DNA / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004247:DNA; D002784:Cholesterol