New potential antitumoral di(hetero)arylether derivatives in the thieno[3,2-b]pyridine series: Synthesis and fluorescence studies in solution and in nanoliposomes

Abstract

New fluorescent methoxylated di(hetero)arylethers in the thieno [3,2-b]pyridine series were prepared by a copper-catalyzed Ullmann-type C-O coupling of the methyl 3-amino-6-bromothieno[3,2b]pyridine-2-carboxylate with ortho, meta and para-methoxyphenols, using N,N-dimethylglycine as the ligand and Cs 2 CO 3 as the base. The compounds obtained were tested for their inhibitory growth activity in three human tumor cell lines MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), NCI-H460 (non-small cell lung cancer). The di(hetero)arylethers bearing a methoxy group in the ortho and meta positions showed very low GI 50 values (1.1−2.5 µM) in all the three tumor cell lines. Their fluorescence properties in solution and when encapsulated in different nanoliposome formulations, composed either by egg-yolk phosphatidylcholine (Egg-PC), dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylglycerol (DMPG), dioctadecyldimethylammonium bromide (DODAB), distearoyl phosphatidylcholine (DSPC), with or without cholesterol (Ch), or distearoyl phosphatidylethanolamine-(polyethylene glycol)2000 (DSPE-PEG), were studied. All compounds can be carried in the hydrophobic region of the liposome membrane. The liposomes with incorporated compounds are nanometric in size (diameter lower than 150 nm) and have generally low polydispersity.

New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

“…The reaction of the 7-bromothieno [3,2-b]pyridine (1), also prepared by us from the commercial thieno [3,2-b]pyridin-7-ol and POBr 3 , with methoxy or fluorophenols and anilines gave rise in moderate to good yields to the new di(hetero)arylethers 2a-f, by a copper-catalyzed (C-O) Ullmann coupling with N,N-dimethyl glycine as the ligand [13], previously used by us in the synthesis of other di(hetero)arylethers [5], and in good to high yields to the new di(hetero)arylamines 3a-f by a palladium-catalyzed (C-N)…”

“…The tumour cell growth inhibitory activity of the di(hetero)arylethers 2a-f and di(hetero)arylamines 3a-f was evaluated in five human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung carcinoma), HCT15 (colon adenocarcinoma), HepG2 (hepatocellular carcinoma) and HeLa (cervical carcinoma) using the sulforhodamine B assay as previously described [2][3][4][5][6][7]. This allowed the determination of the GI 50 values (µM), corresponding to the concentration of the compounds which inhibited 50% of cell growth ( Table 1).…”

“…1H, 6-H), 7.20-7.24 (m, 2H, 3' and 5'-H), 7.29-7.32 (m, 2H, 2' and 6'-H) ii)DMEM supplemented with 10% FBS, 2 mM glutamine, 100 U/mL penicillin and 100 mg/mL streptomycin, for HeLa and HepG2 cells). To assess the growth inhibitory activity of the compounds, the Sulforhodamine B assay was performed according to a procedure previously described by the authors [2][3][4][5][6][7]. For this, each cell line was plated at an appropriate density (7.…”

“…The thienopyridine skeleton has been reported as having interesting biological activities namely antitumoral [1][2][3][4][5][6][7] and antiangiogenic [8][9][10][11][12]. Sugano et al reported that the (3-amino-6-thien-2-yl-thieno [2,3-b]pyridin-2-yl)arylmethanones I showed selectivity against a tumorigenic cell line, in very low EC 50 values [1].…”

“…The compounds with a methoxy group in ortho (VIa) or meta (VIb) relative to the ether function showed very low GI 50 values (1-2.5 µM). These compounds are fluorescent and have been encapsulated into 4 nanoliposomes for drug delivery purposes [5]. In another study, compound Vd showed a very low GI 50 value (1.2 µM) in the HepG2 hepatocellular carcinoma cells with no hepatotoxicity to porcine liver primary cells.…”