Abstract
The mangosteen fruit is a popular Southeast Asian fruit consumed for centuries. There have been a variety of xanthones isolated from the fruit, bark, roots and leaves with each having unique chemical and physical properties. Previously, the most abundant xanthone α-mangostin has been shown to inhibit CDK4. Herein we describe the role of selected xanthones from the mangosteen inhibiting CDK4. The evidence we provide here is that key functional groups are required to inhibit the CDK4 protein to prevent the phosphorylation of downstream targets critical to inhibiting uncontrolled cell cycle progression. To define the properties of xanthones for inhibiting CDK4 we utilized a cell free biochemical assay to identify inhibitors of CDK4. The following xanthones were used for the analysis: α-mangostin, β-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C and garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin These results further substantiate the unique pharmacological properties of individual xanthones and how a mixture of xanthones may be responsible for a multi-targeted effect in cell based pharmacology systems.
Highlights
The purple mangosteen (Garcinia mangostana L.) is a fruit-producing tree that is native to Southeast Asia and has been used for hundreds of years for medicinal purposes 1
The colon cell line HCT 116 was treated with increasing concentrations of xanthones (0 – 100 μM) with the following EC50 calculated for each α-mangostin (23.4), β-mangostin (19.1), γ-mangostin (12.1), gartanin (6.84), 8-desoxygartanin (18.2), garcinone C (27.4), garcinone D (15.8), and 3-isomangostin (47.4)
Several xanthones did not display any significant inhibition of CDK4/Cyclin D1 included: β-mangostin, garcinone C, gartanin, and 8-desoxygartanin
Summary
The purple mangosteen (Garcinia mangostana L.) is a fruit-producing tree that is native to Southeast Asia and has been used for hundreds of years for medicinal purposes 1. Xanthones contain a C6-C1-C6 ring structure, with various isoprene and hydroxyl units branching off the foundational tricyclic structure These units are thought to be important contributors to xanthones’ biological activities 3. There have been more than 70 different xanthones isolated from G. mangostana 3-5, with α-mangostin being the most abundant xanthone found and α-mangostin, β-mangostin, γ-mangostin, gartanin, and 8-desoxygartanin being the most studied xanthones[1]. These xanthones have been shown to have cytotoxic, anti-tumor and anti-cancer activities and here we will present data showing that xanthones inhibit cyclin dependent kinases (CDK’s)[4,5,6,7]
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