New anionic carbosilane dendrons functionalized with a DO3A ligand at the focal point for the prevention of HIV-1 infection

- Novel bifunctionalized carbosilane dendrons with a DO3A at the focal point and anionic peripheral groups have been prepared.
- All compounds show a low cytotoxicity and potent and broad-spectrum anti-HIV-1 activity in vitro.
- Copper-free dendrons 5 and 6 inhibit the HIV-1 infection at the entry through the blockade the binding of gp120 to CD4.
- Copper-free dendrons 5 and 6 show their non-specific ability acting on the virus and interacting with the CD4 cell receptor.

Novel third-generation polyanionic carbosilane dendrons with sulfonate or carboxylate end-groups and functionalized with a DO3A ligand at the focal point, and their corresponding copper complexes, have been prepared as antiviral compounds to prevent HIV-1 infection. The topology enables the compound to have an excellent chelating agent, DO3A, while keeping anionic peripheral groups for a therapeutic action. In this study, the cytotoxicity and anti-HIV-1 abilities of carboxylate- (5) or sulfonate-terminated (6) dendrons containing DO3A and their copper complexes (7 or 8) were evaluated. All compounds showed low cytotoxicity and demonstrated potent and broad-spectrum anti-HIV-1 activity in vitro. We also assessed the mode of antiviral action on the inhibition of HIV-1 through a panel of different in vitro antiviral assays. Our results show that copper-free dendron 6 protects the epithelial monolayer from short-term cell disruption. Copper-free dendrons 5 and 6 exert anti-HIV-1 activity at an early stage of the HIV-1 lifecycle by binding to the envelope glycoproteins of HIV-1 and by interacting with the CD4 cell receptor and blocking the binding of gp120 to CD4, and consequently HIV-1 entry. These findings show that copper-free dendrons 5 and 6 have a high potency against HIV-1 infection, confirming their non-specific ability and suggesting that these compounds deserve further study as potential candidate microbicides to prevent HIV-1 transmission.

196