A series of N-acylhydrazone-linked, heterobivalent β-carboline derivatives was designed and synthesized from l-tryptophan in a nine-step reaction sequence. The effort resulted in the heterobivalent β-carbolines 10a-t in good yields. The target compounds were characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The in vitro cytotoxic activity of the synthesized compounds was evaluated against normal EA.HY926 cells and five cancer cell lines: LLC (Lewis lung carcinoma), BGC-823 (gastric carcinoma), CT-26 (murine colon carcinoma), Bel-7402 (liver carcinoma), and MCF-7 (breast carcinoma). Compound 10e, with an IC50 value of 2.41 μM against EA.HY926 cells, was the most potent inhibitor. It showed cytotoxicity against all five cancer cell lines of different origin - murine and human, with IC50 values ranging from 4.2 ± 0.7 to 18.5 ± 3.1 μM. A study of structure-activity relationships indicated that the influence on cytotoxic activities of the substituent in the R9'-position followed the tendency, 2,3,4,5,6-perfluorophenylmethyl > 4-fluorobenzyl > 3-phenylpropyl group. The antitumor efficacies of the selected compounds were also evaluated in mice. Compound 10e exhibited potent antitumor activity, with tumor inhibition of more than 40% for Sarcoma 180 and 36.7% for Lewis lung cancer. Furthermore, the pharmacological mechanisms showed that compound 10e has a certain impairment in the motility of LLC cells, which suggests the anti-metastatic potential. And compound 10e inhibited angiogenesis in chicken chorioallantoic membrane assay, and the anti-angiogenetic potency was more potent than the reference drug combretastatin A4-phosphate (CA4P) at a concentration 50 μM.
Keywords: Acylhydrazone group; Cytotoxic activity; Heterobivalent β-carboline; Structure-activity relationships.
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