title: Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.
abstract: The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10-dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[(2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N, N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl)ethylamino]-O-tosyl-1-++ +butan ol. All of the hydroxylated analogues were active against L1210 cells with 96-h IC(50) values of </=2 microM, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues on ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., N(1),N(11)-diethylnorspermine [DENSPM]) at 1 microM; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N(1)-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R, R)-(HO)(2)DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (R, R)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Science Center, Gainesville, Florida 32610, USA. bergeron@mc.cop.ufl.edu
authors.forename: R J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: R
authors.initials: R
authors.lastname: Müller
authors.forename: J
authors.initials: J
authors.lastname: Bussenius
authors.forename: J S
authors.initials: JS
authors.lastname: McManis
authors.forename: R L
authors.initials: RL
authors.lastname: Merriman
authors.forename: R E
authors.initials: RE
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.forename: W R
authors.initials: WR
authors.lastname: Weimar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D006900:Hydroxylation; D007939:Leukemia L1210 / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines