| Abstract
| - An efficient five-step synthetic method was developed to access a series of spermine derivativescontaining appended acridine, anthracene, and 7-chloroquinoline motifs. The derivatives werecomposed of a spermine fragment covalently tethered at its N4 and N9 positions to an aromaticnucleus via an aliphatic chain (e.g., 8: acridine −[C4 aliphatic tether]−spermine−[C4 aliphatictether]−acridine). The distance separating the spermine and aromatic nuclei was altered viadifferent tethers composed of four or five methylene units. These bis ligands (8, 9, 12, and 13)were shown to inhibit human DNA topoisomerase II (topo II) activity at 5 μM. Enzymaticactivity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA).Polyamine conjugation did not disrupt the ability of the acridine−spermine conjugates 8 and9 to inhibit topo II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridinecontrols (at 5 μM). The parent polyamines, spermine (5 μM) and spermidine (10 μM), had littleeffect on topo II activity. In general, the bis-substituted spermine derivatives (8, 9, 12, and 13)were more efficient topo II inhibitors at 5 μM than their monosubstituted spermidinecounterparts (22−25) at 10 μM. Within the bisintercalator spermine series, insertion of anadditional methylene unit (i.e., C5 tethers) increased potency 2-fold (8, bis-C4-acridine, 47 hIC50 = 40 μM; 9, bis-C5-acridine, IC50 = 17 μM). Comparison of the bis- and monoacridinespermine motifs (8 and 17) revealed a 4-fold increase in potency for the latter architecture (94h IC50 for 8, 74 μM; for 17, 17 μM). In general the bisintercalators (8, 9, 12, and 13) behavedas cytostatic agents, while the monosubstituted acridine and anthracene derivatives (22−25)were cytotoxic. Anthracene-containing conjugates were generally more toxic than their acridinecounterparts in an L1210 (murine leukemia) cell assay. Of the conjugates tested the(monointercalator)−spermine motif (e.g., 17) had the highest affinity for the L1210 polyaminetransporter as revealed by spermidine protection experiments.
|
