Polyamines and Polyamine Amides as Potent Selective Receptor Probes, Novel Therapeutic Lead Compounds and Synthetic Vectors in Gene Therapy

Abstract

The family of polyamines and polyamine amides, especially unsymmetrical synthetic members, is critically assessed with respect to chemical structure and pharmacological activity. Naturally occurring polyamines (and diamines) and mono- (and di-) acylated polyamines (polyamine amides) are blockers of cation channels that are receptor- or voltage-gated. Such compounds are leads for the design of novel therapeutic agents. Furthermore, polyamines and polyamine amides are templates for the design of synthetic vectors with potential application in gene therapy. Natural di- and polyamines, spider and wasp venom polyamine amide toxins and their analogues, and totally synthetic polyamines, are potent cation-channel blockers with uses as selective receptor probes for nicotinic acetylcholine and glutamate (NMDA and non-NMDA) receptors, sodium and calcium channels. Therefore, as receptor probes, they may help us to understand the molecular mechanisms of neurodegeneration, and ultimately to design drugs for the treatment of neurodegenerative diseases, especially stroke. Polyamine conjugates are also novel therapeutic lead compounds for possible treatments of cancer, diarrhoea, malaria and haemochromatosis (β-thalassaemia). The metal chelating properties of (poly-) ethylenediamines have led to their incorporation in ion chelators which are synthetic RNase and DNase enzymes. Synthetic polyamines and polyamine amides have potential as novel vectors in gene delivery. Such compounds can condense DNA to form toroidal particles which may be incorporated in a non-viral gene delivery system. The applications of polylysine, polyethylenimine, Starburst polyamidoamine dendrimers, Transfectam (DOGS), cholic acid, and cholesterol conjugates to gene therapy are compared as a function of structure and pKa. This assessment of polyamines and polyamine amides stresses the basicity of the amine functional groups. The pKa's of these functionalities are a major determinant in their binding to biological macromolecules. Selectivity of pharmacological action also encompasses contributions from solution conformation and lipophilicity as well as amine pKa. The use of these compounds as leads for the design of novel therapeutics or gene medicines is demonstrated to be practical as well as theoretically possible.