title: Polyamine transport inhibitors: design, synthesis, and combination therapies with difluoromethylornithine.
abstract: The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer cells. Several design features were discovered which strongly influenced PTI potency, sensitivity to amine oxidases, and cytotoxicity. These included changes in (a) the number of polyamine chains appended to the ring system, (b) the polyamine sequence, (c) the attachment linkage of the polyamine to the aryl core, and (d) the presence of a terminal N-methyl group. Of the series tested, the optimal design was N(1),N(1'),N(1″)-(benzene-1,3,5-triyltris(methylene))tris(N(4)-(4-(methylamino)butyl)butane-1,4-diamine, 6b, which contained three N-methylhomospermidine motifs. This PTI exhibited decreased sensitivity to amine oxidases and low toxicity as well as high potency (EC50 = 1.4 μM) in inhibiting the uptake of spermidine (1 μM) in DFMO-treated L3.6pl human pancreatic cancer cells.
authors.affiliation: Department of Chemistry, University of Central Florida , 4000 Central Florida Boulevard, Orlando, Florida 32816-2366, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Muth
authors.forename: Meenu
authors.initials: M
authors.lastname: Madan
authors.forename: Jennifer Julian
authors.initials: JJ
authors.lastname: Archer
authors.forename: Nicolette
authors.initials: N
authors.lastname: Ocampo
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D010190:Pancreatic Neoplasms; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097667:Polyamine Oxidase
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D000518:Eflornithine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase; C000608809:N1,N1',N1''-(benzene-1,3,5-triyltris(methylene))tris(N4-(4-(methylamino)butyl)butane-1,4-diamine