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Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter

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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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Abbreviations

AZ:

Antizyme

CHO:

chinese hamster ovary

CHOMG:

polyamine transport deficient CHO cells

DFMO:

α-difluoromethylornithine

Mel-A:

normal melanocyte cell line

MGBG:

methylglyoxalbis(guanylhydrazone)

ODC:

ornithine decarboxylase

PAT:

polyamine transporter

SPD:

spermidine

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Authors and Affiliations

  1. Department of Chemistry, University of Central Florida, Orlando, FL, USA

    O. Phanstiel IV & N. Kaur

  2. CNRS UMR6061 “Génétique & Dévelopement”, Cell Cycle Group, Faculté de Médecine, Université Rennes, Rennes, France

    J.-G. Delcros

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  1. O. Phanstiel IV
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  2. N. Kaur
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  3. J.-G. Delcros
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Phanstiel, O., Kaur, N. & Delcros, JG. Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter. Amino Acids 33, 305–313 (2007). https://doi.org/10.1007/s00726-007-0527-y

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