Synthesis of lipo-peptide containing somatostatin sequence and their anti-tumor activity — ASN Events
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Synthesis of lipo-peptide containing somatostatin sequence and their anti-tumor activity (#54)

Yuko Tsuda 1 , Koushi Hidaka 1 , Anna Miyazaki 2 , Isoko Kuriyama 3 , Hiromi Yoshida 3 , Yoshiyuki Mizushina 3
  1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo, Japan
  2. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
  3. Faculty of Nutrition, Kobe Gakuin University, Kobe, Hyogo, Japan

Somatostatin-14 (SS-14) related peptide, octreotide (cyclic 8-amino acid peptide) is successfully applied for the treatment of cancers targeting SS-14 receptors (SSTRs) overexpressed on cancer cells. Considerable efforts have been made to develop SS-14 analogue with clinically useable anti-tumor activity. For example, Keri et al. reported that TT-232 [H-D-Phe-c(Cys-Tyr-D-Trp-Lys-Cys)-Thr-NH2], exhibited a potent anti-tumor activity without antisecretory action through SSTRs [1]. Based on its sequence, we synthesized H-Tyr-D-Trp-NH-1-(Ada; adamantane) (YO-14) and reported it exhibited potent anti-tumor activity on human colon carcinoma (HCT116) cells (LD50 = 15.0 microM). A structure-activity relationship analysis revealed that its hydrophobicity could be responsible for the anti-tumor activity.
In this presentation, we described synthesis of lipo-peptides containing the somatostatin sequence and their anti-tumor activities. The lipo-peptide consists of a charged amino acid sequence (Tyr-D-Trp-Lys or TT-232) covalently attached to lipophillic alkyl chain (stearic acid or palmitic acid) through a variety of linkers. The peptides were assembled by a standard Fmoc solid phase peptide synthesis (SPPS) on Fmoc-amide resin. YO-137, in which a palmitic acid bound to the TT-232, through a linker, (AdOOH; 8-amino-3,6-dioxaoctanoic acid)2-Gly, had both anti-tumor activity on HCT116 cells (LD50 = 0.80 microM) and DNA polymerase (pol) inhibitory activity (IC50 = 25 and 4.7 microM for calf pol alpha and rat pol beta, respectively). TT-232 itself exhibited anti-tumor activity (LD50 = 26 microM) without pols inhibition (IC50: >100 microM for calf pol  alpha and rat pol beta). Those findings imply that incorporation of fatty acid is beneficial for the anti-tumor activity as well as the pol inhibition.

[1]Keri, G., Erchegyi, J., Horvath, A., Mezo, I., Idei, M., Vantus, T., Balogh, A., Vadasz, Z., Bokonyi, G., Seprodi, J., Teplan, I., Csuka, O., Tejeda, M., Gaal, D., Szegedi, Z., Szende, B., Roze, C., Kalthoff, H., Ullrich, A. (1996) Proc. Natl. Acad. Sci. USA, 93, 12513-12518.