Design and synthesis of Ampelopsin based CXCR4 ligans as novel anticancer agents.

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CXC-chemokine receptor 4 (CXCR4) together with CC-chemokine receptor 5 (CCR5) and) has been identified as the major HIV co-receptor and therefore represents a promising target for the development of new anti-HIV drugs. Several natural derivatives have been recognized as antagonists of chemokine receptors involved in viral replication. Ampelopsin ((2R,3R)-3,4-dihydro-2,6,8-trihydroxy-3-(3,4,5-trihydroxyphenyl)naphthalene-(2H)-one) (I) is a flavonoid compound isolated from different plants. In particular it represents one of the active compounds produced by Vitis Hederacea. Recent studies reported the anti-HIV effects of this flavonoid and its interaction with the HIV-1 co-receptorCXCR4. In in vitro assays Ampelopsin was shown to possess protective activity in sensitive cells against HIV-1 infection reducing the viral attachment to target cells and inducing a consistent internalization of HIV-1 co-receptor CXCR4. Thus, this low molecular weight natural compound represents a new lead to provide useful insight for the discovery of new CXCR4 antagonists.2Herein, the design and the preparation of novel Ampelopsin derivatives is reported. The addition of a penta-atomic nucleus fused to ring B, replacing the hydroxycarbonyl moiety, as well as the introduction of an oxygen atom on ring B and/or appropriate functional groups on both rings A and C, has been planned.All these modifications should improve the pharmacokinetic profile and the CXCR4 antagonistic activity of the natural reference compound while maintaining a similar overall asset of the molecule, compatible with biological activity.