Synthesis and biological evaluation of N1-(anthracen-9-ylmethyl)triamines as molecular recognition elements for the polyamine transporter

An efficient modular synthesis of N-1-substituted triamines containing different tether lengths between nitrogen centers was developed. A series of N-1-(9-anthracenylmethyl)triamines were evaluated for biological activity in L1210 (murine leukemia), alpha-difluoromethylornithine (DFMO)-treated L1210, Chinese hamster ovary (CHO), and CHO-MG cell lines. All triamines 8 had increased potency in DFMO-treated L1210 cells. The 4,4- and 5,4-triamine systems had the highest affinity for the polyamine transporter (PAT) with L1210 K-i values of 1.8 and 1.7 muM, respectively. This trend was also reflected in the CHO studies. Surprisingly, the respective 4,4- and 5,4-triamine systems, had 150-fold and 38-fold higher cytotoxicity in CHO cells containing active polyamine transporters. Initial microscopy studies revealed the rapid formation of vesicular structures within A375 melanoma cells treated with the N-1-(9-anthracenylmethyl)homospermidine (4,4-triamine) conjugate. In summary, the 4,4- and 5,4-triamines were identified as selective vector motifs to ferry anthracene into cells via the PAT.