Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters
Abbreviated Journal Title
J. Med. Chem.
PREFERENTIAL UPTAKE SYSTEM; L1210 LEUKEMIA-CELLS; ALPHA-DIFLUOROMETHYLORNITHINE; ESCHERICHIA-COLI; MAMMALIAN-CELLS; CHEMOTHERAPEUTIC-AGENTS; ANALOG ANTIDIARRHEALS; BIOLOGICAL EVALUATION; GENE DELIVERY; DNA-BINDING; Chemistry, Medicinal
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-l-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 IC50 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 IC50 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 h ad 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: similar to0.5 muM) in CHO cells, which have an active polyamine transporter (PAT). However, this series had IC50 values of > 100 muM, 66.7 muM, and 15.5 muM, 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 muM. In summary, the 4,4-triamine motif was shown to facilitate entry of polyamine conjugates into cells containing active polyamine transporters.
Journal of Medicinal Chemistry
"Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters" (2003). Faculty Bibliography 2000s. 4106.