Influence of Surface Groups on Poly(propylene imine) Dendrimers Antiprion Activity

Prion diseases are characterized by the accumulation of PrP^Sc, an aberrantly folded isoform of the host protein PrP^C. Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP^Sc in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly­(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP^Sc in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP^Sc by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups

Oxaphosphinanes: New Therapeutic Perspectives for Glioblastoma

This paper reports the design and the synthesis of a new family of compounds, the phostines, belonging to the [1,2]­oxaphosphinane family. Twenty-six compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its easy synthesis and low EC₅₀ value (500 nM against the C6 rat glioma cell line), compound <b>3.1a</b> was selected for further biological study. Moreover, the specific biological effect of <b>3.1a</b> on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, <b>3.1a</b> has a higher antiproliferative activity than Temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, <b>3.1a</b> is devoid of astrocyte toxicity. The original activity spectrum of <b>3.1a</b> on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives