Nitrogen-containing analogs of salinomycin, synthesis and use against cancer stem cells and malaria
A compound and mixture technology, applied in the field of amino derivatives of salinomycin, can solve problems such as peripheral neuropathy and salinomycin neurotoxicity
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Embodiment 1
[0219] Embodiment 1: the synthesis of formula (I) compound
[0220] Preparation of oxidized salinomycin acid (oxo-Sal-H)2:
[0221]
[0222] Salinomycin sodium (2.00 g, 2.587 mmol) was dissolved in 250 mL of DCM, and manganese dioxide (9.00 g, 103.5 mmol, 40 eq) was added. The suspension was stirred overnight at room temperature. After complete conversion of the starting material, the mixture was filtered on celite. with 15mM H 2 SO 4 Aqueous extract filtrate, in MgSO 4 Drying and concentration afforded product 2 (1,71 g, 2.28 mmol, 96%) as pure and white foam without any further purification.
[0223] 1H NMR (CDCl3, 500MHz, rt): 0.64-0.72 (6H, m), 0.72-0.82 (6H, m), 0.83-0.98 (12H, m), 1.04-1.17 (4H, m), 1.19-1.27 ( 2H,m),1.30-1.57(12H,m),1.59-2.05(14H,m),2.43-2.60(2H,m),2.63-2.73(1H,m),2.76-2.88(1H,m),3.38 -3.52(1H,m),3.66(1H,d,J=9.6Hz),3.76(1H,d,J=10.2Hz),3.88-4.04(2H,m),4.11-4.22(1H,m), 6.20 (1H,d,J=10.7), 7.12 (1H,d,J=10.7).
[0224] 13C NMR (CDCl3, 500MHz, rt...
Embodiment 2
[0260] Example 2: IC 50 evaluate
[0261] Cell viability assays were performed by plating in 96-well plates at 1000 cells per well. NAC (2 mM, A9165 Sigma) or DFO (1 mM) were pretreated 2 hours prior to compound treatment. After 24, 48 or 72 hours of treatment, add Reagent (Promega; G3582) (20 μl / well), cells were incubated for 1 hour before recording fluorescence (560(20)Ex / 590(10)Em) using a Perkin Elmer Wallac 1420 Victor2 microplate reader.
[0262] result:
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[0264]
[0265]
[0266]
[0267]
[0268] The above results indicate that compounds without an amine functional group at position 20 are less potent than salinomycin against cancer stem cells.
[0269] Introduction of an amine functional group at position 20 of salinomycin resulted in significantly increased activity against CD24 cells (AM5, AM8, AM11, AM12, AM13 and AM23), up to 18-fold.
[0270] Substitution of the carboxylic acid function at position 1-position of salinomycin with an ...
Embodiment 3
[0273] Example 3: Effects of AM5, AM9 and AM13 on the proliferation of HMLER CD24- cells:
[0274] The ability of AM5, AM9, AM13 and salinomycin to inhibit cell proliferation and formation of non-adherent mammosphere populations was evaluated.
[0275] The results are shown in figure 2 middle.
[0276] At 30nM, AM5 and AM13 inhibit cell proliferation with a ten-fold increase in efficacy compared to salinomycin.
[0277] In contrast, AM 9 did not inhibit cell proliferation even at 500 nM.
[0278] These results therefore show that the compound of formula (I) according to the invention is able to inhibit the formation of non-adherent mammosphere population cells more effectively than salinomycin.
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