(S)-stereoisomer of telomestatin as a potent G-quadruplex binder and telomerase inhibitor.
Total synthesis of the (S)-stereoisomer of telomestatin (1) was accomplished. (S)-Telomestatin exhibited potency four times that of the natural product, (R)-telomestatin, which was the most potent telomerase inhibitor previously reported. In the circular dichroism spectral analysis of the complexes possessing randomly structured single-stranded d[TTAGGG](4) oligonucleotide, (S)-telomestatin, like (R)-telomestatin, induced an antiparallel G-quadruplex structure. The melting temperature (T(m)) value of the (S)-isomer complex was greater than that of the (R)-telomestatin complex. Therefore, it is concluded that the stereochemistry of the thiazoline of telomestatin is important to the binding ability of a G-quadruplex binder, and (S)-telomestatin as a G-quadruplex binder is more potent than the natural product.
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. doi_taka@mail.pharm.tohoku.ac.jp
Takayuki
T
Doi
Kazuaki
K
Shibata
Masahito
M
Yoshida
Motoki
M
Takagi
Masayuki
M
Tera
Kazuo
K
Nagasawa
Kazuo
K
Shin-ya
Takashi
T
Takahashi
D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D054856:G-Quadruplexes; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis*; D013237:Stereoisomerism; D019098:Telomerase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010080:Oxazoles; C431888:telomestatin; D019098:Telomerase