Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter |
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Authors: | O. Phanstiel Suffix" >IV,N. Kaur,J.-G. Delcros |
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Affiliation: | (1) Department of Chemistry, University of Central Florida, Orlando, FL, USA;(2) CNRS UMR6061 “Génétique & Dévelopement”, Cell Cycle Group, Faculté de Médecine, Université Rennes, Rennes, France |
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Abstract: | Summary. A series of polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT) in two Chinese hamster ovary (CHO) cell lines (PAT-active CHO and PAT-inactive CHOMG). This systematic study identified salient features of the polyamine architecture required to target and enter cells via the PAT. Indeed, the separation of charges, the degree of N-alkylation, and the spacer unit connecting the N1-terminus to the appended cytotoxic component (anthracene) were found to be key contributors to optimal delivery via the PAT. Using the CHO screen, the homospermidine motif (e.g., 4,4-triamine) was identified as a polyamine vector, which could enable the selective import of large N1-substituents (i.e., naphthylmethyl, anthracenylmethyl and pyrenylmethyl), which were cytotoxic to cells. The cell selectivity of this approach was demonstrated in B-16 murine melanoma cells and normal melanocytes (Mel-A). Three polyamine areas (recognition and transport, vesicle sequestration and polyamine-target interactions) were identified for future research. |
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Keywords: | : Polyamine – Transport – Anthracene – Cytotoxicity |
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