Synthesis of Cyclo--tripeptides and Their Biological in vitro Evaluation as Antiproliferatives against the Growth of Human Cancer Cell Lines

Abstract

A number of cyclo-β-tripeptides and their linear precursors were subjected to primary biological evaluation for cancer-cell growth inhibition (one-dose, three-cell essay), and the five most active ones were then tested in the anti-tumor screen of the National Cancer Institute (Bethesda, USA) with 60 human cancer cell lines. Growth inhibition values GI50 in the one-digit micromolar, and in one case in the nanomolar range were obtained. The effects show selectivities for certain types of cancer cells and for certain cell lines within these types; the screen includes leukemia, non-small-cell lung, colon, and central-nervous-system (CNS) cancer, melanoma, ovarian, renal, prostate, and breast cancer cell lines. The synthesis and full characterization of two new cyclo-β-peptides, (β3-HSer(OBn))3 (11) and (β3-HMet)3 (12) are described. Other cyclo- β-peptides included in this investigation are (β-Asp(Bn))3 (13), (β-HGlu(Bn))3 (14), and (β-HAla)3 (16), compounds which had been previously prepared by us. Strongest activities were measured with the cyclo-β-peptides bearing benzyl-ester or benzyl-ether groups in the side chains. The cytotoxic activity of the compounds included in this investigation is much lower (LC50>100 μM) than their antiproliferative activity (GI50).