Synthesis and biological evaluation of polyamine vectors as new drug delivery agents

O Phanstiel, PhD

Center for Discovery of Drugs and Diagnostics, Department of Chemistry, University of Central Florida, Orlando, FL

The goal of this research was to evaluate the polyamine transport apparatus as a viable means to deliver drugs to malignant cell types. A structure-activity relationship was developed to relate drug conjugate architecture with efficacy. A series of polyamine vectors were synthesized and appended to either an acridine, anthracene or 7-chloroquinoline nucleus. The acridine and anthracene systems were tested for anticancer activity in L1210 murine leukemia cells, while the 7-chloroquinoline systems were evaluated for anti-malarial activity in Plasmodium falciparum, i.e. the malarial parasite. Diverse toxicity profiles were observed in the series evaluated in L1210 cells with the monoanthracene-spermidine conjugate being the most potent. Conjugates, which contained longer tether lengths separating the drug nucleus from the appended polyamine, were usually more potent. Spermidine-(L1210 cell) rescue experiments revealed differential affinities for the polyamine transporter by the conjugates tested. In some cases the toxicities observed mirrored the conjugates ability to use the polyamine transporter to gain entry to the cell. The effect of polyamine homologation on the transport and toxicity of the chloroquine conjugates was surprising. A tetra-amine architecture, when conjugated to 7-chloroquinoline in the 4-position, significantly reduced the potency of the parent chloroquine system. This finding was consistent with a rapid polyamine-mediated efflux from the parasite. In summary, the efficacy of the two drug classes (i.e. DNA intercalators and chloroquine) were modified by the appended polyamine.

KEY WORDS: cancer, DNA intercalator, malaria, spermidine, spermine, transport.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Gene Therapy, Part 2.