title: Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters.
abstract: Several N(1)-substituted polyamines containing various spacer units between nitrogen centers were synthesized as their respective HCl salts. The N(1)-substituents included benzyl, naphthalen-1-ylmethyl, anthracen-9-ylmethyl, and pyren-1-ylmethyl. The polyamine spacer units ranged from generic (4,4-triamine, 4,3-triamine, and diaminooctane) spacers to more exotic [2-(ethoxy)ethanoxy-containing diamine, hydroxylated 4,3-triamine, and cyclohexylene-containing triamine] spacers. Two control compounds were also evaluated: N-(anthracen-9-ylmethyl)-butylamine and N-(anthracen-9-ylmethyl)-butanediamine. Biological activities in L1210 (murine leukemia), alpha-difluoromethylornithine (DFMO)-treated L1210, and Chinese hamster ovary (CHO) and its polyamine transport-deficient mutant (CHO-MG) cell lines were investigated via IC(50) cytotoxicity determinations. K(i) values for spermidine uptake were also determined in L1210 cells. Of the series studied, the N(1)-benzyl-4,4-triamine system 6 had significantly higher IC(50) values (lower cytotoxicity) in the L1210, CHO, and CHO-MG cell lines. A cellular debenzylation process was observed in L1210 cells with 6 and generated "free" homospermidine. The size of the N(1)-arylmethyl substituent had direct bearing on the observed cytotoxicity in CHO-MG cells. The N(1)-naphthalenylmethyl, N(1)-anthracenylmethyl, and N(1)-pyrenylmethyl 4,4-triamines had similar toxicity (IC(50)s: approximately 0.5 microM) in CHO cells, which have an active polyamine transporter (PAT). However, this series had IC(50) values of >100 microM, 66.7 microM, and 15.5 microM, respectively, in CHO-MG cells, which are PAT-deficient. The observed lower cytotoxicity in the PAT-deficient CHO-MG cell line supported the premise that the conjugates use PAT for cellular entry. In general, moderate affinities for the polyamine transporter were observed for the N-arylmethyl 4,4-triamine series with their L1210 K(i) values all near 3 microM. In summary, the 4,4-triamine motif was shown to facilitate entry of polyamine conjugates into cells containing active polyamine transporters.
authors: Groupe de Recherche en Therapeutique Anticancéreuse, Faculté de Médecine, 2, Avenue du Professeur Léon Bernard, University of Rennes 1, 35043 Rennes, France.
authors: Chaojie
authors: C
authors: Wang
authors: Jean-Guy
authors: JG
authors: Delcros
authors: Laura
authors: L
authors: Cannon
authors: Fanta
authors: F
authors: Konate
authors: Horacio
authors: H
authors: Carias
authors: John
authors: J
authors: Biggerstaff
authors: Richard Andrew
authors: RA
authors: Gardner
authors: Otto
authors: O
authors: Phanstiel IV
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D001593:Benzyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006224:Cricetinae; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011721:Pyrenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D002352:Carrier Proteins; D009281:Naphthalenes; D011073:Polyamines; D011721:Pyrenes