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 microM, 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.