title: Lower rim guanidinocalix[4]arenes: macrocyclic nonviral vectors for cell transfection.
abstract: Guanidinium groups were introduced through a spacer at the lower rim of calix[4]arenes in the cone conformation to give new potential nonviral vectors for gene delivery. Several structural modifications were explored, such as the presence or absence of a macrocyclic scaffold, lipophilicity of the backbone, length of the spacer, and nature of the charged groups, in order to better understand the factors which affect the DNA condensation ability and transfection efficiency of these derivatives. The most interesting compound was a calix[4]arene unsubstituted at the upper rim and having four guanidinium groups linked at the lower rim through a three carbon atom spacer. This compound, when formulated with DOPE, showed low toxicity and transfection efficiency higher than the commercially available lipofectamine LTX in the treatment of human Rhabdomiosarcoma and Vero cells. Most of the investigated compounds showed a tendency to self-aggregate in pure water or in the presence of salts, as evidenced by NMR and AFM studies, and it was found that the ability to condense DNA plasmids in nanometric globules is a necessary but not sufficient condition for transfection. The superiority of macrocyclic vectors over linear Gemini-type analogues and of guanidinium compared to other ammonium head groups in determining the biological activity of the vectors was also ascertained.
authors.affiliation: Dipartimento di Chimica Organica e Industriale, Università di Parma , Parco Area delle Scienze 17/A, I-43124, Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bagnacani
authors.forename: Valentina
authors.initials: V
authors.lastname: Franceschi
authors.forename: Laura
authors.initials: L
authors.lastname: Fantuzzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Casnati
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
authors.forename: Francesco
authors.initials: F
authors.lastname: Sansone
authors.forename: Rocco
authors.initials: R
authors.lastname: Ungaro
mesh_terms: D000818:Animals; D047250:Calixarenes / Q000737:chemistry*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage*; D019791:Guanidine / Q000031:analogs & derivatives*; D006801:Humans; D010636:Phenols / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage*; D012995:Solubility; D014162:Transfection; D014709:Vero Cells
chemical_list: D010636:Phenols; C121325:calix(4)arene; D047250:Calixarenes; D004247:DNA; D019791:Guanidine