165288-15-3Relevant academic research and scientific papers
Polyamine derivatives as inhibitors of trypanothione reductase and assessment of their trypanocidal activities
O'Sullivan, Mary C.,Zhou, Qibing,Li, Zhili,Durham, Timothy B.,Rattendi, Donna,Lane, Schennella,Bacchi, Cyrus J.
, p. 2145 - 2155 (2007/10/03)
Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the andoxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with K(i) values of 3.5, 5.5 and 9.5 μM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 μM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique gathway in Trypanosomatidae have potential as antitrypanosomal agents.
The Role of Charge in Polyamine Analogue Recognition
Bergeron, Raymond J.,McManis, James S.,Weimar, William R.,Schreier, Katherine M.,Gao, Fenglan,et al.
, p. 2278 - 2285 (2007/10/02)
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 and N,N'-bis-1,4-diaminobutane , and their aromatic counterparts, N,N'-bis(4-pyridylmethyl)-1,4-diaminobutane and N,N'-bis-1,4-diaminobutane .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.
