Polyamine Transport Inhibitors: Design, Synthesis, and Combination Therapies with Difluoromethylornithine

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• 作者：Aaron Muth ; Meenu Madan ; Jennifer Julian Archer ; Nicolette Ocampo ; Luis Rodriguez ; Otto Phanstiel ; IV
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 23, 2014
• 年：2014
• 卷：57
• 期：2
• 页码：348-363
• 全文大小：669K
• ISSN：1520-4804

文摘

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 N¹,N^{1鈥?/sup>,N1鈥?/sup>-(benzene-1,3,5-triyltris(methylene))tris(N4-(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 渭M) in inhibiting the uptake of spermidine (1 渭M) in DFMO-treated L3.6pl human pancreatic cancer cells.}