The Effect of Polyamine Homologation on the Transport and Cytotoxicity Properties of Polyamine−(DNA-Intercalator) Conjugates

Abstract

An efficient five-step synthetic method was developed to access a homologous series of spermidine-acridine and spermidine-anthracene conjugates. The derivatives were comprised of a spermidine fragment covalently tethered at its N4 position to either an acridine or anthracene nucleus via an aliphatic chain (e.g., spermidine-[aliphatic tether]-acridine). The distance separating the spermidine and aromatic nucleus was altered by using different tethers comprised of four or five methylene units, respectively. These ligands (2-5) were shown to inhibit human DNA topoisomerase-II (TOPO-II) activity at 10 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermidine conjugates 2 and 3 to inhibit TOPO-II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 10 microM). In general, the acridine derivatives (2 and 3) showed higher TOPO-II inhibitory activity than their anthracene counterparts (4 and 5). However, this trend was reversed in a whole cell assay with L1210 (murine leukemia) cells, wherein the anthracene analogues were more potent than their acridine counterparts. In this regard the qualitative enzyme-based assay did not predict the trends in the corresponding IC(50) values. Within either series insertion of an additional methylene unit did not significantly alter activity. While the appended spermidine unit did not disrupt TOPO II inhibition by the tethered DNA intercalator, it did provide an alternative mode of entry into the cell as demonstrated by spermidine protection assays. These results were compared with a spermine-intercalator analogue. Of all the conjugates tested the N(4)-(4-(9-aminoacridinyl)butyl)spermine hexahydrochloride (conjugate 16)resulted in the highest degree of L1210 cell rescue upon cotreatment of the cells with exogenous spermidine. It was concluded that the monoalkylated spermine motif present in 16 holds promise as a better vector than its N4 monoalkylated spermidine counterpart.

Synthesis of novel naphthoquinone-spermidine conjugates and their effects on DNA-topoisomerases I and II-alpha

“…Although a number of PA conjugates have been described in the literature, 6,8,[22][23] to our knowledge, these are the first naphthoquinone spermidine adducts known to date. Preliminary results of the relaxation assays of DNA topo I and II-α indicate that the enzyme topo II-α is a target of PA-naphthoquinone conjugates 2b-4b at relatively low concentrations, and also point to the importance of the naphthoquinone moiety in improving the inhibitory activity of PA 1a.…”

“…5 Anticancer therapies have tried to use the PAT to convey citotoxic and genotoxic agents to rapidly proliferating cells. 6 …”

“…linear tricyclic systems) whose primary target is a DNA topoisomerase enzyme. 6,8 As part of our interest in the synthesis of PAs 9 and in the preparation of aminonaphthoquinone derivatives with pharmacological activities, 10,11 we became interested in linking spermidine (1) to lapachol (2), nor-lapachol (3) and lawsone (4). The prenyl naphthoquinone 2 is readily isolated from several species of Tabebuia sp (Bignoniaceae) abundant in South America, and derivative 3 is obtained from 2 by the Hooker oxidative degradation.…”

Arm effects of mononuclear armed cyclen copper complexes on DNA cleavage

“…Anthracene derivatives, in particular, have received considerable attention as potential antitumor drugs [21][22][23][24][25]. For example, spacerlinked anthraquinone-amino acid conjugates, capable of binding to DNA by intercalation of the planar aminoanthraquinone ring system, were confirmed to have experimental in vivo activity against colon cancer [26][27][28].…”

Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy

“…5 Thus, several 9-aminoacridine derivatives have been synthesized and demonstrated to have high anti-tumor activity. [6][7][8] Copyright # 2005 John Wiley & Sons, Ltd.…”