Noncyclam Tetraamines Inhibit CXC Chemokine Receptor Type 4 and Target Glioma-Initiating Cells

Abstract

The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the meso form 1(S,R)) and their corresponding tetrahydrochlorides 11 were prepared from (S)- and (R)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC(50) values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower K(B) for AMD3100, with the 1(R,R) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice.

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“…ICT5040, compound 1 , also reduces CXCL12-induced proliferation of U87-glioma cells in a concentration dependent manner (Figure 14) consistent with the involvement of chemotactic axes in glioma proliferation[64,65]. We first showed that this receptor is expressed on the human glioma U87-MG cells (see file S2), and that the cell proliferation rates increase in response to CXCL12, the ligand for CXCR4 (Figure 14).…”

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“…11 More recently, we have synthesized three stereoisomers of compound 5 (5(R,R), 5(S,S), and the meso form 5(S,R)) and evaluated their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. 14 Through our research and previous ones, a paradigm has been widely accepted: to use the p-phenylene moiety as the central core for the connection of nitrogen heterocycles linked to two nitrogen atoms on both sides of such a core. This paradigm, the presence of a single carbon atom between the central phenyl ring and the first nitrogen of the side chain, comes from the study of Bridger et al 15 who showed that, in the case of analogues 6 (Fig.…”

“…3). The corresponding synthetic itineraries (Scheme 1) use 1,4-benzenediacetic acid (9) and 2-(4-(bromomethyl)phenyl)acetic (14) acid, respectively, and a library of amines of the general structure 12{x} as starting materials.…”

“…As stated above for 7{1,1}, but using the borane dimethylsulfide complex (1.19 mL, 11.89 mmol), N,N′-bis (3-(4-methylpiperazin-1-yl) (15). To a solution of 0.235 g (1 mmol) of 2-(4-(bromomethyl)phenyl)acetic acid (14) in 10 mL of toluene was added 0.385 g (3.2 mmol) of thionyl chloride. The mixture was heated to 90°C for 6 hours to obtain a yellow solution.…”

“…Finally, the reduction of amides 13{x,x} with BH 3 ·SMe 2 in THF yielded the desired symmetrical tetramines 7{x,x} (Scheme 1). In order to obtain the non-symmetrical compounds 8{x,y}, we selected 2-(4-(bromomethyl)phenyl)acetic acid (14) as the starting material (Scheme 1) due to the different reactivity of the two ends of the molecule which allows the derivatization of both positions with the same or different amines 12{x} to afford compounds 8{x,x} and 8{x,y}, respectively. Thus, the first amine 12{x} was introduced by acylation with acid chloride 15, prepared by treating 14 with SOCl 2 /toluene.…”