Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter.
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 N(1)-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 N(1)-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.
Phanstiel
O
O
Department of Chemistry, University of Central Florida, Orlando, FL 32816-2366, USA. ophansti@mail.ucf.edu
Kaur
N
N
Delcros
J-G
JG
D000818:Animals; D000873:Anthracenes / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D008546:Melanoma, Experimental; D011073:Polyamines / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D002352:Carrier Proteins; D011073:Polyamines