Peptidyl anthraquinones as potential anticancer drugs: synthesis, telomerase inhibition, and biological activity

• Main Authors: Wu Jia-Er, 吳家爾
• Other Authors: Huang Hsu-Shan
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/93479864363921207639

碩士 === 國防醫學院 === 藥學研究所 === 95 === Telomerase is the enzymatic activity that maintains the ends of eukaryotic chromosomes. Telomerase activity is detected in most tumor cells whereas it is low or undetectable in most normal somatic cells. The composition of human telomerase consists of two molecules each of TRC (Telomere RNA Component) and TERT (Telomere Reverse Transcriptase). TRC is a single RNA molecule, which provides an AAUCCC (in mammals) as template. TERT is a reverse transcriptase, which is a class of enzyme that creates single stranded DNA using single stranded RNA as a template. Expression of the telomerase catalytic component, the human telomerase reverse transcriptase (hTERT), is believed to be controlled primarily at the level of transcription. Because of this selective expression property of telomerase, it has been touted as a specific target for antitumor chemotherapeutics. In the path, our laboratory investigate telomerase inhibitory, cytotoxicity and the hTERT repressing effects on synthesizing 2,6-diamidoanthraquinones and 1,5-diamidoanthraquinones as compared to their disubstituted homologues. We found that several of the 1,5-diamidoanthraquinones and 2,6-diamidoanthraquinones inhibited telomerase activity effectively with IC50 at the sub-micro to micro molar range and caused acute cytotoxicity to cancer cells with EC50 similar or better than that of mitoxantrone. Therefore, our laboratory synthesis another series of 1,4- 1,5- 2,6- 2,7-diamidoanthraquinone derivatives (peptidyl anthraquinone). By synthesizing a series of 1,4- 1,5- 2,6- 2,7- peptidyl anthraquinone derivatives, we can study human telomerase reverse transcriptase (hTERT), telomeric repeat amplification protocol (TRAP). We use SEAP assay and MTT assay to monitor the hTERT expression; we can evaluate if compounds can inhibit the activity of telomerase by a mechanism consistent with interaction with G-quadruplex structure. On the other hand, some literature points out that aminoanthraquinone can against cancer cell by inhibiting topoisomerase II. The results suggested that these compounds caused multiple effects to cancer cells. Hence we synthesize a series of peptidyl anthraquinone derivatives hope to find some effective compounds.