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Astins, a family of cyclopentapeptides, isolated from the roots of a medicinal plantAster tataricus(Compositae), show antitumour activity. Their chemical structures consist of a 16-membered ring system containing a unique β,γ-dichlorinated proline [Pro(Cl2)], other non-coded amino acid residues, and acisconformation in one of the peptide bonds. The β,γ-dichlorinated proline residue is considered to play an important role in their antineoplastic activitiesin vitroon nasopharynx carcinoma (KB) cells andin vivoon sarcoma 180 ascites and P388 lymphocytic leukaemia in mice. The acyclic astins without Pro(Cl2) do not show antitumour activity against S-180 ascitesin vivo, suggesting that the cyclic nature of astins plays an important role in their antitumour activities. We synthesized new astin-related cyclopeptides differing from the natural product for the presence of some non-proteinogenic amino acid residues: Aib, Abu, -S(β3)-hPhe and a peptide bond surrogate (−SO2−NH−) and we tested for their antitumour effect. We observed cytotoxic effects of the newly synthesized cyclic astins, but not with the acyclic analogue astins. We also observed that the cyclic astin induced apoptosis in a human papillary thyroid carcinoma cell line (NPA cell line) and that apoptotis was associated with activation of caspases. The caspase family inhibitor, Z–Val–Asp–(OMe)–FMK, protected NPA cells from cyclic analogue astin-induced apoptosis. To determine which caspase was specifically activated, we assayed caspase activity in astin-treated cells in the presence of specific caspase and 8, 9 or 3 inhibitors, i.e. Z–IETD–FMK, Z–LEHD–FMK Z–DEVD–FMK, which inhibit caspases 8, 9 and 3, respectively. The data presented here show selective antineoplastic properties of the newly synthesized cyclic astins, and suggest, for the first time, a mechanism for their antineoplastic action through the activation of apoptotic pathway.

Antineoplastic cyclic astin analogues kill tumour cells via caspase-mediated induction of apoptosis