Conformationally Restricted Analogues of ¹N,¹²N-Bisethylspermine:  Synthesis and Growth Inhibitory Effects on Human Tumor Cell Lines

Abstract

Eight analogues of 1N,12N-bisethylspermine (BES) with restricted conformations were synthesized in the search for new spermine mimetics with cytotoxic activities. By replacing the central butane segment of BES with a 1,2-disubstituted cyclopropane ring, a pair of cis/trans-isomers was obtained that introduced a spatial constraint in the otherwise freely mobile butane chain. An analogous pair of isomers was obtained when the butane segment was replaced with a 1, 2-disubstituted cyclobutane ring or with a 2-butene residue. The six new BES analogues thus obtained (three pairs of cis/trans-isomers) were growth inhibitory at low-micromolar concentrations against four human tumor cell lines (A549, HT-29, U251MG, and DU145) but were less growth inhibitory against two other human tumor cell lines (PC-3 and MCF7). 1N,12N-Bisethylspermyne, where the central butane segment of BES was replaced by the rigid 2-butyne segment, was devoid of growth inhibitory activity against five of the six human cell lines studied (DU145 being the only exception), a clear indication of the importance of conformational mobility at the 4N, 9N-butane segment of BES for its biological activity. When the butane segment was replaced by a benzene-1,2-dimethyl residue, the resulting BES analogue was devoid of growth inhibitory activity despite its cisoid conformation. The cytotoxicity of the analogues does not seem to be directly related to their uptake by the cells or to their effects on cellular polyamine levels. BES analogues with restricted conformations but which contained the equivalent of a two-carbon unit, rather than the natural four-carbon unit, at the central segment, such as 1,2-diaminocyclopropyl or 1, 2-diaminocyclobutyl derivatives, were devoid of growth inhibitory effects at the concentrations studied. The development of conformationally restricted polyamine analogues appears to show promise in the further quest for polyamine-related therapeutic agents with specificity of action.

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]). In an attempt to overcome the limitations encountered with specific inhibitors of enzyme function, we and others have exploited the self-regulatory properties of polyamine metabolism for therapeutic advantage through the use of structural analogues of the natural polyamines [4,5,8,18,39,43,44,49]. The initial studies with polyamine analogues, particularly with BENSpm, were promising, but clinical trials with a number of analogues in lung, breast, and other tumors did not reveal efficacy as single agents.…”

“…CGC-11047 has shown positive results in the treatment of nonHodgkin's lymphoma and is currently in several clinical trials. Treatment with CGC-11047 has demonstrated significant growth inhibition in numerous tumor cell lines with ID 50 s as low as 50 nM in DU145 cells [43]. The growth inhibition was concurrent with analogue accumulation and decreased natural polyamines.…”

“…The growth inhibition was concurrent with analogue accumulation and decreased natural polyamines. However, the basis for this decrease in polyamine pools was not determined [43]. Consequently, despite some very promising results with CGC-11047, further studies on its biochemistry and potential mechanism of action are needed.…”

The Effects of Conformational Constraints in the Polyamine Moiety of Philanthotoxins on AMPAR Inhibition

“…The HT structure is believed to be the most active at AMPARs due to previous observations showing that the monocationic analogues are virtually inactive at AMPARs. [4,14] In terms of general shape mono-cationic analogues are "folded" because they do not possess a "tail" at all. Our modelling studies show that for all compounds the vast majority (99.8%) of low-energy conformations possessed at least one intramolecular H-bond.…”

“…The commonly used solution-phase method for obtaining polyamines displaying a cyclopropane moiety is alkylation of mesitylenesulfonamides with mesitylenesulfonates of cyclopropane diols, but this is not readily transferred into an SPS protocol due to the harsh conditions required for deprotonation of the sulfonamide and the risk of cross-linking the resin due to the bifunctional building block. [14] Cyclopropane-trans-1,2-dicarboxylic acid [15] may be readily obtained from the corresponding ethyl diester and the cisanhydride 3-oxabicyclo[3.1.0]hexane-2,4-dione was commercially available, and therefore, we chose an approach involving on-resin reduction of the diamide corresponding to the desired 4,4'-dimethoxytrityl-protected polyamine. [16] In the present work we focus on incoporating unprecedented structural variations of the polyamine moiety present in both 1 and its well-studied close structural analogue, PhTX-343 (2), and examine how these influence the inhibitory effects of the resulting PhTX analogues on a specific subunit, GluA1flop, present in members of the AMPAR subdivision of the ionotropic glutamate receptor family.…”