10-Alkoxy-anthracenyl-isoxazole analogs have sub-micromolar activity against a Glioblastoma multiforme cell line

Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters

“…The cytotoxicity studies performed on human glioma cells (SNB-19 cells) using 10-alkoxy-anthracenyl-isoxazole analogues, outlined in Figure 2, provide evidence that the unsymmetrical 2,10-dimethoxy AIM has an improved antitumor activity over the symmetrical 10-methoxy AIM. Additionally, the computational docking experiments, also noted in Figure 2, suggest that there exists a preference for the (M)-atropisomer over the (P)-atropisomer, with the M conformer having a more favorable binding energy as well as assigned interaction for the (M)-2-methoxy substituent, which exhibited an interaction with the dG8 sugar-phosphate backbone (Figure 3A) [7]. Although computational docking is not a direct reflection of nature, these results combine to indicate a promising route to increased activity through the synthesis of unsymmetrical and conformationally locked atropisomers.…”

“…As our experimental studies of the process continued, the interaction with DNA G-quadruplex structures, via a combination of stacking with the G-decks, and interactions with the sugar-phosphate backbone and extrahelical bases, was supported by G4 DNA melting experiments, 2D NMR titration studies, computational docking, and molecular dynamics experiments [6]. We have previously reported the quadruplex-binding small molecules known as AIMs have displayed tumor growth inhibition in the micro-to sub-micromolar range against breast cancer, as well as human and rat glioma cell lines [5][6][7]. Most recently, we expanded our working hypothesis to the ternary complex of G4, with its helicase in combination with the antitumor AIM [7].…”

“…We have previously reported the quadruplex-binding small molecules known as AIMs have displayed tumor growth inhibition in the micro-to sub-micromolar range against breast cancer, as well as human and rat glioma cell lines [5][6][7]. Most recently, we expanded our working hypothesis to the ternary complex of G4, with its helicase in combination with the antitumor AIM [7]. In recent generations of AIM small molecules, we have addressed the bioavailability concerns revolving around the lipophilicity of the anthracene moiety [6] and continued to develop the structure-activity relationship and increase the potency [5][6][7].…”

“…Most recently, we expanded our working hypothesis to the ternary complex of G4, with its helicase in combination with the antitumor AIM [7]. In recent generations of AIM small molecules, we have addressed the bioavailability concerns revolving around the lipophilicity of the anthracene moiety [6] and continued to develop the structure-activity relationship and increase the potency [5][6][7]. However, one main concern raised in the pursuit of G-4 quadruplexes as viable therapeutic targets is the structural similarity and ubiquitous presence of quadruplexes in all cell types that could lead to unwanted polypharmacology [1].…”

Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells

“…Recently, 10-anthryloxy-isoxazole-pyrrole-doubletails (RO-AIMs) have shown promise as antitumor drugs. Based on in silico analysis, it has been postulated that RO-AIMs exert their effect by interacting with the DEAH-Box helicase 36 (DHX36) and c-Myc in a ternary complex, halting glioma cell proliferation [410] (Table 1).…”