Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives

Abstract

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.

Iron chelation promoted by desazadesferrithiocin analogs: An enantioselective barrier

“…For the IC 50 measurements, 42 cells were grown in 25-cm 2 tissue culture flasks in a total volume of 10 ml. Cultures were treated during logarithmic growth (0.…”

Spermine analogue-regulated expression of spermidine/spermine N1-acetyltransferase and its effects on depletion of intracellular polyamine pools in mouse fetal fibroblasts

“…We did not study the activity of AdoMetDC (S-adenosylmethionine decarboxylase) the other key enzyme in the biosynthesis of polyamines in this study. However, it has been shown previously that DENSpm and CPENSpm reduce the activity of AdoMetDC, while CHENSpm does not [4,33]. Therfore the low intracellular polyamine levels in DENSpm- and CPENSpm-treated cells could partly reflect reduced biosynthesis, but in the case of CHENSpm some additional mechanisms, including direct replacement from binding sites and the transport system, need to be considered.…”

Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

“…We have seen this consistently over the years with nearly all polyamine analogues. 7f However, L1210 cells exposed to chelators or polyamine chelator conjugates always present with very similar 48- and 96-h IC 50 values. 9 This is consistent with the idea that the ethyl ester chelator conjugate 7 is gaining intracellular access and the chelator is being released.…”

“…Culture were treated during logarithmic growth (0.5–1.0 × 10 5 cells/mL) with the compounds of interest, reseeded, and incubated as described previously. 7g Cell counting and calculation of percent of control growth were also carried out as given in an earlier publication. 7g The IC 50 is defined as the concentration of compound necessary to reduce cell growth to 50% of control growth after defined intervals of exposure.…”

“…The sustained increases in polyamine biosynthesis in pre-neoplastic and neoplastic tissues led to a great deal of attention focused on the polyamine biosynthetic network as a target in antineoplastics therapy. 5 In the course of developing N -alkylated analogues of the natural polyamines as anticancer drugs, 6,7 the structural boundary conditions set by the polyamine transporter on these substrates were defined. All of the findings, 8,9 are consistent with the idea that charge is critical to transporter recognition of the polyamine analogues.…”