title: Designing the polyamine pharmacophore: influence of N-substituents on the transport behavior of polyamine conjugates.
abstract: N-Ethylated N-arylmethyl polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT). To understand the effect of N-ethylation upon PAT selectivity, ethyl groups were appended onto a PAT-selective N (1)-anthracenenylmethyl homospermidine derivative, 1b. Bioevaluation in L1210 murine leukemia cells and in two Chinese hamster ovary cell lines (PAT-active CHO and PAT-deficient CHO-MG) revealed a dramatic decrease in PAT targeting ability upon N (1) or N (5) ethylation of the pharmacophore 1b. Experiments using the amine oxidase inhibitor, aminoguanidine (AG, 2 mM), revealed that the N (9)-ethyl and N (9)-methyl analogues were able to retain their PAT selectivity and cytotoxicity properties in the presence or absence of AG. In contrast, the lead compound 1b (containing a terminal NH 2 group) revealed a dramatic reduction in both its PAT-targeting ability and cytotoxicity in the absence of AG. An improved balance between these three properties of PAT-targeting, cytotoxicity and metabolic stability can be attained via N-methylation at the N (9)-position.
authors: Groupe Cycle Cellulaire, CNRS UMR 6061 Génétique et Développement, IFR 97 Génomique Fonctionnelle et Santé, Faculté de Médecine, Université Rennes 1, 2 Av. du Pr Leon Bernard, CS 34317, F-35043 Rennes Cédex, France.
authors: Navneet
authors: N
authors: Kaur
authors: Jean-Guy
authors: JG
authors: Delcros
authors: Jennifer
authors: J
authors: Archer
authors: Nathan Z
authors: NZ
authors: Weagraff
authors: Bénédicte
authors: B
authors: Martin
authors: Otto
authors: O
authors: Phanstiel Iv
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011073:Polyamines / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D011073:Polyamines; C004479:pimagedine