Designing the polyamine pharmacophore: Influence of N-substituents on the transport behavior of polyamine conjugates
Abbreviated Journal Title
J. Med. Chem.
BIOLOGICAL EVALUATION; MAMMALIAN-CELLS; SPERMIDINE/SPERMINE; N-1-ACETYLTRANSFERASE; MOLECULAR REQUIREMENTS; SELECTIVE DELIVERY; SPERMINE ANALOGS; HIGH-AFFINITY; SYSTEM; PROLIFERATION; CYTOTOXICITY; Chemistry, Medicinal
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 Ib (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.
Journal of Medicinal Chemistry
"Designing the polyamine pharmacophore: Influence of N-substituents on the transport behavior of polyamine conjugates" (2008). Faculty Bibliography 2000s. 525.