Title

N1-Substituent Effects In The Selective Delivery Of Polyamine Conjugates Into Cells Containing Active Polyamine Transporters

Abstract

Several N1-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N 1-substituents evaluated ranged in size from N1-benzyl, N1-naphthalen-1-ylmethyl, N1-2-(naphthalen-1-yl)ethyl, N1-3-(naphthalen-1-yl)propyl, N1-anthracen-9-ylmethyl, N1-2-(anthracen-9-yl)ethyl, N1-3-(anthracen-9-yl)propyl, and pyren-1-ylmethyl. The polyamine architecture was also altered and ranged from diamine to triamine and tetraamine systems. Biological activities in L1210 (murine leukemia), Chinese hamster ovary (CHO), and CHO's polyamine transport-deficient mutant (CHO-MG) cell lines were investigated via IC 50 cytotoxicity determinations. Ki values for spermidine uptake were also determined in L1210 cells. The size of the N 1-arylalkyl substituent as well as the polyamine sequence used had direct bearing on the observed cytotoxicity profiles. N1-Tethers longer than ethylene showed dramatic loss of selectivity for the polyamine transporter (PAT) as shown in a CHO/CHO-MG cytotoxicity screen. In summary, there are clear limits to the size of N1-substituents, which can be accommodated by the polyamine transporter. A direct correlation was observed between polyamine-conjugate uptake and cytotoxicity. In this regard, a cytotoxicity model was proposed, which describes a hydrophobic pocket of set dimensions adjacent to the putative PAT polyamine-binding site.

Publication Date

11-18-2004

Publication Title

Journal of Medicinal Chemistry

Volume

47

Issue

24

Number of Pages

6055-6069

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm0497040

Socpus ID

8644275508 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/8644275508

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