ABSTRACT
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.
Subject(s)
Dendrimers/chemistry , Dendrimers/pharmacology , Polypropylenes/chemistry , Polypropylenes/pharmacology , PrPSc Proteins/antagonists & inhibitors , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Cell Line , Dendrimers/therapeutic use , Mice , Mice, Transgenic , Polypropylenes/therapeutic use , PrPSc Proteins/metabolism , Prion Diseases/drug therapy , Prion Diseases/metabolism , Surface PropertiesABSTRACT
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 EC(50) value (500 nM against the C6 rat glioma cell line), compound 3.1a was selected for further biological study. Moreover, the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a 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, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclic P-Oxides/chemical synthesis , Organophosphonates/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Brain Neoplasms/drug therapy , Cell Count , Cell Line, Tumor , Cell Survival/drug effects , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/pharmacology , Drug Screening Assays, Antitumor , Glioblastoma/drug therapy , Humans , Organophosphonates/chemistry , Organophosphonates/pharmacology , Phosphorous Acids , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In drug discovery, structural modifications over the lead molecule are often crucial for the development of a drug. Herein, we reported the first in vivo bioisosteric effect of phosphinolactone function in relation to the lactol group constituting the bioactive molecule: Hydroxybupropion. The preparation of phosphinolactone analogues and their antidepressant evaluation towards forced swimming test in mice showed that biological activity was regained and even strengthen.
