New antitumor cyclic astin analogues: Synthesis, conformation and bioactivity

Astins, antitumor cyclic pentapeptides, were isolated from the Aster tataricus. Their chem. structures, consist of a 16-membered ring system contg. a unique b,g-dichlorinated proline [Pro(Cl)2], other non-coded amino acid residues and a cis conformation in one of the peptide bonds. The astin backbone conformation, along with the cis peptide bond in which the b,g-dichlorinated proline residue is involved, was considered to play an important role in their antineoplastic activities on sarcoma 180A and P388 lymphocytic leukemia in mice, but the scope and potential applications of this activity remain unclear. With the aim at improving our knowledge of the conformational properties influencing the bioactivity in this class of compds., new astin-related cyclopeptides were synthesized differing from the natural products by the presence of some non-proteinogenic amino acid residues: Aib (aminoisobutyric acid), Abu (aminobutanoic acid), -(S)b3-hPhe and a peptide bond surrogate (-SO2-NH-). The analogs prepd. c(-Pro-Thr-Aib-b3-Phe-Abu-), c[Pro-Thr-Aib-(S)b3-hPhe-Abu], c[Pro-Abu-Ser-(S)b3-hPhey(CH2-SO2-NH)-Abu] and c[Pro-Thr-Aib-(S)b3-hPhey(CH2-SO2-NH)-Abu] were synthesized by classical methods in soln. and tested for their antitumor effect. These mols. were studied by crystal-state X-ray diffraction anal. and/or soln. NMR and MD techniques.