Synthesis and evaluation of novel spermidine derivatives as targeted cancer chemotherapeutic agents

Abstract

The utility of the spermidine moiety as the homing device for the selective delivery of chemotherapeutic and diagnostic agents into cancer cells was explored. Two spermidine analogs containing a cytotoxic agent were synthesized, N-[3,4-bis(benzyloxy)phenethyl]-N alpha-(3-amino-propyl)-L-ornithinamide trihydrochloride, 1a and N-[4-]bis(2-chloroethyl)amino]phenethyl]-N alpha-(3-aminopropyl)-L- ornithinamide tetrahydrochloride, 1b. These compounds were prepared from the fully protected spermidine molecule with a carboxyl group side chain, 8. The ability of the polyamine cytotoxic agents to inhibit B16-BL6 melanoma cell growth in culture was examined. The effects of pretreatment with DFMO on the activity of the synthesized compounds was also studied. The IC50 values of compounds 1a and 1b were on the same order of magnitude as the control compounds, N-acetyldopamine and chlorambucil, respectively. The inhibitory activities of compounds 1a and 1b were not enhanced by pretreatment with DFMO, suggesting that depletion of intracellular polyamines did not enhance the activity of these compounds.

Chemical highlights of polyamine transport

“…cells [4], neuroblastoma cells [ 51, B 16 melanoma cells [6], human colonic [7] and lung tumour [8] cell lines, cultured human lymphocytic leukaemia cells [9], Erhlich ascites tumour cells [lo], L1210 cells [ l l ] and ADJ/PC6 plasmacytoma cells [12]. Exploiting both the transport mechanism and the presumed high affinity of polyammonium cations for DNA, we [12] and others [13] have attempted to develop a general strategy for targeting the DNA of cancer cells. Although polyamines are clearly essential to promote cell growth, it is still not clear what role polyamine uptake from extracellular sources might play and how polyamine analogues might disrupt this.…”

A Charge-Deficient Analogue of Spermine with Chelating Properties

“…Other reagents were manufactured in Russia. N-Benzyloxycarbonyl-3-aminopropanol was prepared as described in [22].…”

Mechanism of dansylation of the polyamine pentaazapentacosane ·5 HCl

“…Polyamine moieties have also been used as a template for attaching cytotoxic agents. In this way the polyamine transport system can be used to increase the intracellular concentrations of antineoplastic agents (Symons, 1995;Stark, et. al.…”