Development of potential anticancer agents that target the telomere sequence.
The immortality of cancer cells is due to the relatively high concentration of telomerase enzyme that maintains the telomere sequence during cell division. Human telomeric DNA consists of repeats of the sequence d(5'-TTAGGG-3'). Deoxyribonucleic guanidine (DNG) is a DNA analog in which positively charged guanidine [-NH-C(NH2+)-NH-] replaces the negatively charged phosphodiester of DNA. The synthesized DNG hexamer AgAgTgCgCpC and dodecamer AgAgTgCgCgCAgAgTgCgCpC are complementary to the non-coding telomere sequence d(5'-TTAGGG-3'). We have found that binding of the complementary DNG hexamer to the telomere is favored over that of DNA telomere by 10(2.5)-fold and binding the dodecamer with 2-mismatched DNA is favored by 10(5)-fold. We have shown that DNG binding to RNA is favored over binding to DNA. A complementary complex of DNG with RNA at the active site of telomerase enzyme would be very stable.
Park
Myunji
M
Department of Chemistry and Biochemistry, University of Califonia at Santa Barbara, 93106, USA.
Bruice
Thomas C
TC
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000187:drug effects* / Q000235:genetics*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006146:Guanidines; D009838:Oligodeoxyribonucleotides; C088820:deoxynucleic guanidine; D004247:DNA; D019098:Telomerase