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

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).