Terminally alkylated polyamine analogues as chemotherapeutic agents.

Abstract

which are found in significant amounts in nearly every prokaryotic and eukaryotic cell type. Despite the ubiquitous nature of these compounds, the precise roles that polyamines play in cellular physiology are still being defined, with new avenues for research arising continuously. As a result, there are active research programs focusing on polyamine metabolism in an extremely diverse set of disciplines. The pathways for polyamine metabolism have been elucidated for a relatively small number of organisms. There are important interspecies differences in polyamine metabolism, especially between eukaryotic cells, plants, and some bacteria and protozoa. In some prokaryotes, only putrescine and spermidine are synthesized, while in other cases, such as certain thermophilic bacteria, polyamines with chains longer than spermine are found. In some parasitic organisms, there are additional enzymes which are not present in the host cell and, as such, provide a target for the design of specific antiparasitic agents. However, the enzymes involved in human and mammalian polyamine metabolism are reasonably similar, and inhibitors targeted to these enzymes rely on the observation that polyamine metabolism is accelerated and polyamines are required in higher quantities, in target cell types. The diversity of biological research in the polyamine field is the subject of an excellent book by Seymour Cohen.1 This Perspective will deal with the use of polyamine analogues as chemotherapeutic agents, i.e., the use of synthetic polyamine analogues as anticancer or antiinfective agents. The reader should be aware of additional areas of polyamine research (polyamines as modulators of the NMDA receptor, polyamine-based venoms, polyamines as potential carriers for drug delivery, polyamines used in boron-neutron capture therapy, etc.) which are beyond the scope of this review. The polyamine pathway represents an important target for chemotherapeutic intervention, since depletion of polyamines results in the disruption of a variety * Address correspondence to: Patrick M. Woster, Ph.D, Dept. of Pharmaceutical Sciences, 539 Shapero Hall, Wayne State University, Detroit, MI 48202. Tel: 313-577-1523. Fax: 313-577-2033. E-mail: woster@wizard.pharm.wayne.edu. † Johns Hopkins Oncology Center. § Wayne State University. Figure 1. Structures of the natural polyamines: putrescine (1), spermidine (2), and spermine (3). © Copyright 2001 by the American Chemical Society