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Eur J Med Chem. 2017 Feb 15;127:643-660. doi: 10.1016/j.ejmech.2016.10.026. Epub 2016 Oct 21.

Synthesis, structure-activity relationships and biological evaluation of 7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic agents.

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Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy.
Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128, Padova, Italy.
Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy. Electronic address:


A small library of 7-pyrrolo[3,2-f]quinolinones was obtained by introducing benzoyl, sulfonyl and carbamoyl side chains at the 3-N position, and their cytotoxicity against a panel of leukemic and solid tumor cell lines was evaluated. Most of them showed high antiproliferative activity with GI50s ranging from micro-to sub-nanomolar values, and these values correlated well with the inhibitory activities of the compounds against tubulin polymerization. Based on a recently proposed colchicine bind site inhibitors (CBSIs) pharmacophore, the interactions of the novel 7-PPyQs at the colchicine domain were rationalized. The most active compounds (4a and 4b) did not induce significant cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. In particular, 4a was a potent inducer of apoptosis in both the HeLa and Jurkat cell lines. On the other hand, the sulfonyl derivative 4b exhibited a lower potency in comparison with 4a. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, suggesting that cells treated with the compounds followed the intrinsic pathway of apoptosis.


Apoptosis; Microtubules; Molecular docking; Phenylpyrroloquinolinone; Structure-activity relationships; Tubulin

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