Development of Polyamine Transport Ligands with Improved Metabolic Stability and Selectivity against Specific Human Cancers

Abstract

Polyamine homeostasis is critical for life and is accomplished via a balance of polyamine biosynthesis, degradation, and transport. Rapidly dividing cancer cells have been shown to have high polyamine transport activity compared to normal cells, likely due to their high requirement for polyamine metabolites. The polyamine transport system (PTS) is a therapeutically relevant target, as it can provide selective drug delivery to cancer cells. This report describes the synthesis and biological evaluation of multimeric polyamine derivatives as efficient PTS ligands. Arylmethyl-polyamine derivatives were synthesized to address two important concerns in PTS drug design: (a) PTS selectivity and (b) stability to amine oxidases. N(1),N(1')-[Naphthalene-1,4-diylbis(methylene)]bis{N(4)-[4-(methylamino)butyl])butane-1,4-diamine}, 3b, was found to have an optimal balance between these parameters and demonstrated excellent targeting of melanoma (e.g., MALME-3M) and breast cancer cells (e.g., T47D) over other cancer cell lines. These results provide a method to selectively target cancers via their intrinsic need for polyamine metabolites.

A Study on the Intramolecular Mitsunobu Reaction of N6‐(ω‐Hydroxyalkyl)adenines

“…1 H NMR (300 MHz, CDCl 3 ): δ 1.65 (m, 4H, −CH 2 CH 2 –), 2.43 (s, 3H, CH 3 ), 2.63 (t, J = 6.0 Hz, 2H, CH 2 ), 3.57 (t, J = 6.0 Hz, 2H, CH 2 ), 3.74 ppm (bs, 2H, OH, NH). Data are in agreement with .…”

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

“…Having in mind that monosubstituted diamines have been described as polyamine transport inhibitors [51–53], a possible action mechanism could involve oxidation to activate the compound that then inhibit the polyamine transport.…”

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo

“…Moreover, in the structure of CHENSpm and CPENSpm, the alkylation of the distant nitrogen in the polyamine chain plays an important role in increasing the activity in cancer cells and decreasing the toxicity in normal cells. Our group and others find that natural products with homospermidine moiety without the alkylation of the distant nitrogen in the polyamine chain showed good activities (Casero and Marton, 2007;Wang et al, 2012;Muth et al, 2013Muth et al, , 2014Li et al, 2016Li et al, , 2018Dai et al, 2017a;Ma et al, 2017aMa et al, ,b, 2018Skruber et al, 2017;Casero et al, 2018;Phanstiel, 2018;Liu et al, 2019). However, naphthalimide conjugates with the alkylation of the distant nitrogen in the polyamine chain are rarely reported.…”

“…Resurgence in the interest of natural polyamines as an anticancer strategy results from advances in our understanding of polyamine metabolism and their alterations in cancer (Casero and Marton, 2007;Casero et al, 2018;Phanstiel, 2018). Natural products with polyamine moiety have been found to be a promising strategy to enhance targeting properties and deduce the toxicities (Muth et al, 2013(Muth et al, , 2014Skruber et al, 2017). Polyamine analogs CHENSpm and CPENSpm in Figure 1 have entered in clinical trials.…”