The polyamines putrescine, spermidine and spermine are ubiquitous polycationic compounds that are found in nearly every cell type, and are required to support a wide variety of cellular functions. The existence of multiple cellular effector sites for naturally occurring polyamines implies that there are numerous targets for polyamine-based therapeutic agents. Through a programme aimed at the synthesis and evaluation of biologically active polyamine analogues, our laboratory has identified three distinct structural classes of polyamine derivatives that exhibit promising biological activity in vitro. We have synthesized more than 200 symmetrically and unsymmetrically substituted alkylpolyamines that possess potent antitumour or antiparasitic activity, depending on their backbone architecture and terminal alkyl substituents. Along similar lines, we have developed novel polyamino(bis)guanidines and polyaminobiguanides that are promising antitrypanosomal agents and that interfere with biofilm formation in the pathogenic bacterium Yersinia pestis. Finally, we recently reported a series of PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) that inhibit HDACs (histone deacetylases), and in some cases are selective for individual HDAC isoforms. These studies support the hypothesis that polyamine-based small molecules can be developed for use as biochemical probes and as potential therapies for multiple diseases.
Enzymes in the biosynthetic and catabolic polyamine pathway have long been considered targets for drug development, and early drug discovery efforts in the polyamine area focused on the design and development of specific inhibitors of the biosynthetic pathway, or polyamine analogues that specifically bind DNA. More recently, it has become clear that the natural polyamines are involved in numerous known and unknown cellular processes, and disruption of polyamine functions at their effector sites can potentially produce beneficial therapeutic effects. As new targets for polyamine drug discovery continue to evolve, the rational design of polyamine analogues will result in more structurally diverse agents. In addition, the physical linkage of polyamine-like structures to putative drug molecules can have beneficial effects resulting from increases in DNA affinity and selective cellular uptake. The present chapter will summarize recent advances in the development of alkylpolyamine analogues as antitumour agents, and describe subsequent advances that have resulted from incorporating polyamine character into more diverse drug molecules. Specifically, new polyamine analogues, and the role of polyamine fragments in the design of antiparasitic agents, antitumour metal complexes, histone deacetylase inhibitors and lysine-specific demethylase 1 inhibitors, will be described.
Solid Phase Synthesis (SPS) is a chemical strategy that was developed and refined by Bruce Merrifield in the early 1960s and later led to a Nobel Prize in 1984. This discovery paved the way for chemists to be able to construct proteins with high yields, less timeconsuming purification and much faster synthetic routes. The strategy utilizes an insoluble solid polystyrene cross-linked support resin, 2-chlorotrityl-chloride (2-CCR), to form an ester linkage with an acid so proteins or small molecules can be built from the N terminal one amino acid at a time. This same chemistry can be employed to construct peptidomimetics and small non-peptide molecules. This chemistry is especially useful for building molecules that require temporary protection of a carboxylic acid during the synthetic route. This article will provide the basic concepts and considerations when practicing SPS for small non-peptide molecule construction. Significant considerations in employing this chemistry include: resin selection, swelling of resin, coupling agents, solvents, mechanism, loading of resin, nucleophilic substitution, and cleavage from resin support, amine protecting groups, general reaction techniques as well as purification of final product.
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