Synthesis And Antitumor Activity Of Novel Amino Acids-oriented Pseudo-Peptides

This article combined nature tryptamine and steroid with amino acids on the basis of peptide skeleton structure to seek for novel and efficiency of small molecule structure. A serious of novel pseudo-peptides were designed, synthesized, and evaluated for their inhibition activities against cell proliferation, which may provide some basic data for the development of novel small molecule antitumor drug leads. Detailed general structures are as follows:1. On account of the extensive pharmacological activities of natural source tryptamine, 22 novel pseudo-peptides bearing tryptamine moiety were designed and synthesized, linking tryptamine and amino acids with peptide skeleton structure. All the compounds were characterized by 1H NMR and ESI-MS, evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on antitumor activities, 15 of the newly prepared compounds displayed significantly inhibition activities against human hepatoma cancer(Hep G2 and Huh-7), human melanoma(A875) cell lines, and 5 of them displayed better inhibition activities than the control 5-fluorouracil. Compound I-1c showed the strongest inhibitory effect against Hep G2, with an IC50 value of 8.81 μg/m L; compound I-1h showed the strongest inhibitory effect against Huh-7 and A875 with IC50 values of 3.02, 7.48 μg/m L, respectively. In addition, some of the compounds were evaluated for their in vitro cytotoxic effects against BEL-7402 cell line, to which 5-FU is resistant(IC50 >100 μg/m L). The screening result indicated that all of the compound except I-2c showed pretty inhibition(IC50<14 μg/m L), among which compound I-1h might be developed as novel lead scaffold for potential antitumor agents with an IC50 value of 4.88 μg/m L.2. Sterol compounds are a kind of important natural active substances with good medicinal activity, which widely exists in the organism. Therefore, a series of 25 novel pseudo-peptides bearing dehydroepiandrosterone moiety were designed, synthesized and characterized by pharmacophores hybridization. According to the preliminary studies on antitumor activities, 23 of the newly prepared compounds displayed significantly inhibition activities against human hepatoma cancer(Hep G2), human lung cancer(A549), human melanoma(A875) cell lines compared with the control 5-fluorouracil(IC50<19 μg/m L).Especially, compounds II-1k and II-1i exhibited obvious inhibition activities against all tested cell lines with an IC50 under 7.5 μg/m L. Through further annexin V-FITC experiment, II-1k was tentatively probed. The results revealed that the induction to cell death in Hep G2 cells by highly potential compound II-1k was achieved at least partly via apoptosis.