Title

Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters

Authors

Authors

C. J. Wang; J. G. Delcros; L. Cannon; F. Konate; H. Carias; J. Biggerstaff; R. A. Gardner;O. Phanstiel

Comments

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Abbreviated Journal Title

J. Med. Chem.

Keywords

PREFERENTIAL UPTAKE SYSTEM; L1210 LEUKEMIA-CELLS; ALPHA-DIFLUOROMETHYLORNITHINE; ESCHERICHIA-COLI; MAMMALIAN-CELLS; CHEMOTHERAPEUTIC-AGENTS; ANALOG ANTIDIARRHEALS; BIOLOGICAL EVALUATION; GENE DELIVERY; DNA-BINDING; Chemistry, Medicinal

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-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 Title

Journal of Medicinal Chemistry

Volume

46

Issue/Number

24

Publication Date

1-1-2003

Document Type

Article

Language

English

First Page

5129

Last Page

5138

WOS Identifier

WOS:000186572800005

ISSN

0022-2623

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