Quercetin (Q1) is a flavonol wich belongs to a class of flavonoids and it is present in plants such as Ginkgo Biloba, Aesculus Hippocastanum and Hypericum Perforatum1 and various foods and beverages (onions, apples, broccoli, berries, green tea, and red wine).Quercetin is a versatile molecule, with many pharmacological properties: antioxidant, antiviral, antimicrobial, anti-inflammatory, hepatoprotective, protective of the reproductive systems and cardiovascular apparatus, anti-obesity.Recently, the study of Quercetin as potential anticancer agent is assuming increasing importance considering its involvement in many tumor-related processes, including oxidative stress, apoptosis, proliferation and metastasis.However, the main limitation is the low solubility and chemical stability, so it is very essential to further design, synthesize and screen new derivatives holding improved solubility, pharmacodynamic and pharmacokinetic properties.2For these reasons, in order to enhance the lipophilic character of Q1 and, thus, improve its bioavailability, we prepared a small library of Q1 analogues in which the OH groups have been totally or partially replaced by hydrophobic functional groups.3 We evaluated the anticancer activity of Q1 structural analogues against two lines of breast cancer cells, MCF-7 and MDA-MB-231 cells.Q1 and its analogues exerted a surprisingly higher antitumor activity in the triple negative MDA-MB-231 cells, with respect to the less metastatic and invasive MCF-7 cells. Some of these compounds (Q3 and Q4) exerted important cytotoxic effects on MCF-10a cells viability, whereas Q1 and the other analogues showed a little or no effect.Moreover, compounds Q1-Q5 inhibited the human Topoisomerases I and II (hTopoI and hTopoII) activity, evaluated through an in vitro inhibition assay and molecular docking studies; on the contrary, Q6-Q9 did not affect the activity of hTopoI and hTopoII. The most active compounds, Q2 and Q5, induced cancer cell death by apoptosis and radical oxygen species production, because of DNA damage. At last, Q2 and Q5 exhibit ROS scavenging activity in non-tumoral cells treated with menadione, as well as Q1, even though in a lesser.References:1Sharma M., Sasvari Z., Nagy P.D., Inhibition of sterol biosynthesis reduces tombusvirus replication in yeast and plants, J Virol 84, 2270-81, 2010.2Kim M. K., Park K., Chong Y., Remarkable Stability and Cytostatic Effect of a Quercetin Conjugate, 3,7-Bis-O-Pivaloxymethyl (POM) Quercetin, ChemMedChem 7, 229–232, 2012.3Grande F., Ortensia I. Parisi O. I., Mordocco R. A., Rocca C., Puoci F., Scrivano L., Quintieri A.M., Cantafio P., Ferla S., Brancale A., Saturnino C., Cerra M. C., Sinicropi M. S., Angelone T. Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization. European Journal of Pharmaceutical Sciences 82, 161–170, 2016.
Quercetin Derivatives: evaluation of anti-proliferative activity and inhibition of human Topoisomerases I and II
Ceramella J;Puoci F;GRANDE, Fedora;SINICROPI, Maria Stefania
2017-01-01
Abstract
Quercetin (Q1) is a flavonol wich belongs to a class of flavonoids and it is present in plants such as Ginkgo Biloba, Aesculus Hippocastanum and Hypericum Perforatum1 and various foods and beverages (onions, apples, broccoli, berries, green tea, and red wine).Quercetin is a versatile molecule, with many pharmacological properties: antioxidant, antiviral, antimicrobial, anti-inflammatory, hepatoprotective, protective of the reproductive systems and cardiovascular apparatus, anti-obesity.Recently, the study of Quercetin as potential anticancer agent is assuming increasing importance considering its involvement in many tumor-related processes, including oxidative stress, apoptosis, proliferation and metastasis.However, the main limitation is the low solubility and chemical stability, so it is very essential to further design, synthesize and screen new derivatives holding improved solubility, pharmacodynamic and pharmacokinetic properties.2For these reasons, in order to enhance the lipophilic character of Q1 and, thus, improve its bioavailability, we prepared a small library of Q1 analogues in which the OH groups have been totally or partially replaced by hydrophobic functional groups.3 We evaluated the anticancer activity of Q1 structural analogues against two lines of breast cancer cells, MCF-7 and MDA-MB-231 cells.Q1 and its analogues exerted a surprisingly higher antitumor activity in the triple negative MDA-MB-231 cells, with respect to the less metastatic and invasive MCF-7 cells. Some of these compounds (Q3 and Q4) exerted important cytotoxic effects on MCF-10a cells viability, whereas Q1 and the other analogues showed a little or no effect.Moreover, compounds Q1-Q5 inhibited the human Topoisomerases I and II (hTopoI and hTopoII) activity, evaluated through an in vitro inhibition assay and molecular docking studies; on the contrary, Q6-Q9 did not affect the activity of hTopoI and hTopoII. The most active compounds, Q2 and Q5, induced cancer cell death by apoptosis and radical oxygen species production, because of DNA damage. At last, Q2 and Q5 exhibit ROS scavenging activity in non-tumoral cells treated with menadione, as well as Q1, even though in a lesser.References:1Sharma M., Sasvari Z., Nagy P.D., Inhibition of sterol biosynthesis reduces tombusvirus replication in yeast and plants, J Virol 84, 2270-81, 2010.2Kim M. K., Park K., Chong Y., Remarkable Stability and Cytostatic Effect of a Quercetin Conjugate, 3,7-Bis-O-Pivaloxymethyl (POM) Quercetin, ChemMedChem 7, 229–232, 2012.3Grande F., Ortensia I. Parisi O. I., Mordocco R. A., Rocca C., Puoci F., Scrivano L., Quintieri A.M., Cantafio P., Ferla S., Brancale A., Saturnino C., Cerra M. C., Sinicropi M. S., Angelone T. Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization. European Journal of Pharmaceutical Sciences 82, 161–170, 2016.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
