title: N1-substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters.
abstract: Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthracen-9-yl)ethyl, N(1)-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. K(i) 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. N(1)-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 N(1)-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.
authors.affiliation: Department of Chemistry, P.O. Box 162366, University of Central Florida, Orlando, FL 32816-2366, USA.
authors.forename: Richard Andrew
authors.initials: RA
authors.lastname: Gardner
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Delcros
authors.forename: Fanta
authors.initials: F
authors.lastname: Konate
authors.forename: Fred
authors.initials: F
authors.lastname: Breitbeil
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Sigman
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D009154:Mutation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D002352:Carrier Proteins; D009281:Naphthalenes; D011073:Polyamines