The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA-intercalator) conjugates

    Authors

    O. Phanstiel; H. L. Price; L. Wang; J. Juusola; M. Kline;S. M. Shah

    Comments

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    Abbreviated Journal Title

    J. Org. Chem.

    Keywords

    CHLORAMBUCIL-SPERMIDINE CONJUGATE; POTENTIAL ANTITUMOR AGENTS; TOPOISOMERASE-II; DNA-BINDING; STRAND BREAKS; CELL-LINES; ASSAY; DERIVATIVES; ADRIAMYCIN; COMPLEX; Chemistry, Organic

    Abstract

    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-ll (TOPO-II) activity at 10 mu M 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 mu M) 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 made 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.

    Journal Title

    Journal of Organic Chemistry

    Volume

    65

    Issue/Number

    18

    Publication Date

    1-1-2000

    Document Type

    Article

    Language

    English

    First Page

    5590

    Last Page

    5599

    WOS Identifier

    WOS:000089310200017

    ISSN

    0022-3263

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