The role of charge in polyamine analog recognition

Abstract

A series of analogues and homologues of N1,N12-diethylspermine (DESPM) was synthesized, and their biological properties were evaluated. These tetraamines include a simple linear analogue of DESPM, N1,N12-bis(2,2,2-trifluoroethyl)spermine (FDESPM), the cyclic analogues of DESPM, N,N'-bis(4-piperidinylmethyl)-1,4-diaminobutane [PIP(4,4,4)] and N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane [PIP(5,4,5)], and their aromatic counterparts, N,N'-bis-(4-pyridylmethyl)-1,4-diaminobutane [PYR(4,4,4)] and N,N'-bis[2-(4-pyridyl)ethyl]-1,4-diaminobutane [PYR(5,4,5)]. The analogues FDESPM, PIP(4,4,4), and PYR(4,4,4) have distances between their nitrogen atoms almost identical to those of DESPM. The longer analogues PIP(5,4,5) and PYR(5,4,5) are very similar in the spacing of their amino groups. However, the pKa of the nitrogens in the groups differ; thus, the extent of protonation and the charge characteristics among the members of the groups differ. A comparison of the biological properties of these compounds clearly demonstrates that the tetraamines must be charged to be "recognized" by the cell. Analogues with low nitrogen pKa's such that the nitrogens are poorly protonated at physiological pH do not compete well with spermidine for uptake and, as expected, have high 96 h IC50 values and have little effect on S-adenosylmethionine decarboxylase, ornithine decarboxylase, and spermidine/spermine N1-acetyltransferase activities and on intracellular polyamine pools.

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

“…[131] used the intermediate 57 to obtain the SPD derivatives 51 and 58 whereas Bergeron et al [58,133] used the intermediates 59 and 60 to obtain the PA derivatives 51 and 61 and the SPM analogue 62 ( Figure 13). The Boc groups were delivered using the reagents Boc 2 O or Boc-ON, whereas the Bn and Z(NO 2 ) groups were removed by catalytic hydrogenolysis.…”

“…Weakly charged PA analogues cannot compete with natural PAs for transport through the cell membranes. [58] PAs bearing bulky alkyl substituents on the terminal nitrogen atoms are not efficiently transported, whereas the distance between the nitrogen functions appears to play an important role in their recognition by the PA uptake system. [58,59] Parallel work has been carried out in procaryotic cells.…”

“…[59][61] Bergeron et al have shown that the diethylation of the terminal nitrogens of PA molecules is one of the most effective modifications of the natural PA skeleton towards cancer cell cytotoxicity. [58,62] The therapeutic effect of diethyl analogues appears not to be affected by the presence of exogenous PAs. The most promising analogues of this type, which are already under clinical trials, are N 1 ,N 15 -Et 2 -4,12-diaza-1,15-diaminopentadecane (DE-3-7-3),…”

“…This compound was then used to obtain the diprotected SPD derivatives 97؊99, [148] which are versatile intermediates in the synthesis of SPD conjugates. Other examples include the preparation of PYR(4,4,4) by Bergeron et al, [58] the synthesis by Ganem et al of nonmetabolizable derivatives of SPM and SPD, such as 100, [149] and the assembly of the highly potent cytotoxic DNA crosslinking agent 32 by Callery et al through reductive alkylation of PUT with the aldehyde 101. [79] Recently, reductive alkylation has been frequently used in the assembly of the PA skeleton of complex PA conjugates, for example the hispidospermin (20) and spider and wasp toxins.…”

Antiprotozoal/Antiparasitic Agents

“…A number of N-(3-phenylpropyl) substituted spermine analogs have been reported that act as potent inhibitors of TR [146]. It has been suggested that alkyl-and aralkyl-substituted polyamine analogs disrupt polyamine metabolism because the nitrogen pK a values have been altered, leading to reductions in their degree of protonation at physiological pH [21,147,148]. A key advantage to these compounds as antiparasitic agents is that they selectively enter proliferating cells using the trypanosomal polyamine transport system, where they down regulate the biosynthetic enzymes ODC and AdoMet-DC.…”