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Synthesis and Biological Evaluation of New Geiparvarin Derivatives
Author(s) -
Chimichi Stefano,
Boccalini Marco,
Salvador Alessia,
Dall'Acqua Francesco,
Basso Giuseppe,
Viola Giampietro
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900009
Subject(s) - methyl group , cell culture , chemistry , stereochemistry , in vitro , apoptosis , cell growth , reactive oxygen species , biological activity , growth inhibition , transmembrane protein , inhibitory postsynaptic potential , efflux , biochemistry , alkyl , biology , receptor , organic chemistry , genetics , neuroscience
New geiparvarin derivatives modified at the alkenyloxy bridge, where the 3′‐methyl group was replaced by a hydrogen atom, were synthesized and evaluated against a panel of human tumor cell lines in vitro. Compounds ( R )‐ 4 and ( R )‐ 5 show greater inhibitory activity toward cell growth than the parent geiparvarin.New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3′‐methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geiparvarin. The activity increased even further in the series of demethylated compounds, with the introduction of a methyl group at the 1′‐position of the alkenyloxy chain. In contrast, a remarkable decrease in activity was observed with the introduction of a methyl group at the 2′‐position. Interestingly, the new derivatives fully inhibited the growth of drug‐resistant cell lines, suggesting that they are not subject to pump‐mediated drug efflux. On the basis of their cytotoxic profiles, the most active compounds ( R )‐ 4 and ( R )‐ 5 were selected for further biological evaluation in comparison with the lead compound. The new derivatives strongly induce apoptosis in a promyelocytic leukemia cell line (HL‐60) mediated by depolarization of mitochondrial transmembrane potential and mitochondrial production of reactive oxygen species (ROS).