ChemMedChem
10.1002/cmdc.201700145
COMMUNICATION
Western blot analysis in the more sensitive GPER+ ER- SKBR3
cells showed that treatment for 24 hours with 14b,c,f,g and 15g,
resulted in a significant reduction in the protein levels of Cyclin
D1. Our results revealed that 14b increased the expression of
both p53 and p21 while 14c,f,g, 15g increased the expression of
p21 but not of p53. Treatment with the same compounds for 48
hours showed a sustained increase of p21 and p53 expression
only for compound 14c. On the other hand, Cyclin D1 levels
were reduced by treatment with all the selected compounds
either at 24 and 48 hours. In HEK293 cells, no significant
modulation of p53, p21 and cyclin D1 levels were seen after
treatment for 24 and 48 hours (Figure 4). On the basis of the
preliminary results herein presented, 14c can be considered as
the most promising hit compound endowed with i)
antiproliferative activity in GPER expressing cell lines similar to
G15; ii) reduction in Cyclin D1 expression, one the most
important proteins involved in cell cycle progression in breast
cancer; iii) sustained induction of the cell cycle negative
regulators p53 and p21.
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a
specific
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Further in vitro studies on the synthesized compounds allowed
to identify the pyrrolo[1,2-a]quinoxaline 14c as the most
interesting molecule for an hit-to-lead optimization campaign
aimed at the development of new agents for the treatment of
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Acknowledgements
This work has been supported by the University of Parma (to
MR). We also tank the European Cooperation in Science and
Technology for COST Action CM1207 GLISTEN.
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Keywords: GPER • estrogen • breast cancer • pyrrolo[1,2-
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a]quinoxaline • 5-dihydropyrrolo[1,2-a]quinoxaline
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