Synthesis of 2-anilinopyridyl–triazole conjugates as antimitotic agents

Abstract

A series of 2-anilinopyridyl–triazole conjugates (6a–t) were prepared and evaluated for their cytotoxic activity against a panel of three human cancer cell lines. Among them compounds 6q, 6r and 6s showed significant cytotoxic activity with IC50 values ranging from 0.1 to 4.1 μM. Structure–activity relationships were elucidated with various substitutions on these conjugates. Flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2/M phase and induce cell death by apoptosis. The tubulin polymerization assay and immunofluorescence analysis showed that these compounds (6q, 6r and 6s) effectively inhibited the microtubule assembly in human prostate cancer cells (DU-145). The docking studies showed that 6s interacts and binds efficiently with the tubulin protein at the colchicine binding site. This was further confirmed by the colchicine competitive binding assay. Moreover, compounds 6q, 6r and 6s possess anti-tubulin activity both in vitro and within cells as demonstrated by the ratio of soluble versus polymerized tubulin. Further the apoptotic effects of compounds were confirmed by Hoechst staining, caspase 3 activation, annexin-V FITC, mitochondrial membrane potential and DNA fragmentation analysis. Interestingly, these compounds did not affect the normal human embryonic kidney cells, HEK-293.

Synthesis and Evaluation of 5-Chloro-2-Methoxy-N-(4-Sulphamoylphenyl) Benzamide Derivatives as Anti-cancer Agents

“…To evaluate whether the anti-proliferative effect of 4j is a consequence of cell cycle effects, MIA PaCa-2 cells were exposed to each compound at the concentration of 5x or 10 × GI 50 µM for a period of 24 hours, and the cell cycle effects were Figure 1, the treatment with E7010 resulted in a substantial accumulation of MIA PaCa-2 cells at the G2/M phase (54.7 and 55.7% at 2.5 and 5 µM, respectively) compared to the untreated cells (28.7% in the G2/M). This is consistent with the tubulin targeting mechanism of E7010 [36][37][38][39]. Similarly, 4j increased in the population of the G2/M cells (~ 42%) at concentrations of 10 (5 × GI 50 µM) and 20 µM (10 × GI 50 µM), suggesting a similar but weaker cellular mechanism compared to E7010.…”

Synthesis and biological evaluation of acylated oligorhamnoside derivatives structurally related to mezzettiaside-6 with cytotoxic activity

“…19 K562 cells were growtharrested for 24 h and stimulated with increasing concentrations from 0.5 to 2 μM of compound 1 for the next 48/72 h in DMEM (10% FBS). Mitochondria play an essential role in the propagation of apoptosis.…”

“…To the cold solution, n-octanol (3.6 g, 27.7 mmol) solution in CH 3 CN was added dropwise over a period of 30 min. The residue was purified by silica gel column chromatography (5 : 1, petroleum ether-EtOAc) to give a white solid 16 (3.0 g, 86%); 1 19.0 mmol), Et 3 N (4.0 mL, 28.0 mmol), and DMAP (114 mg, 1.0 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. After the reaction was complete, as judged by TLC, the reaction was quenched with water (30 mL) and extracted with CH 2 Cl 2 (3 × 200 mL).…”

“…The reaction was stirred for an additional 30 min while warming to room temperature. The crude product was purified by silica gel column chromatography (5 : 1, petroleum ether-EtOAc) to afford 4 (2.5 g, 74%) as a white solid; 1 (19). The chloroform layer was washed with saturated aqueous NaHCO 3 (2 × 300 mL), and brine (2 × 300 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure.…”

Design, Synthesis and Biological Evaluation of 2-Anilinopyridyl-Linked Oxindole Conjugates as Potent Tubulin Polymerisation Inhibitors

“…The conjugates 6 r and 6 y were further evaluated by Annexin V FITC/PI (AV/PI) dual staining assay to examine the occurrence of phosphatidylserine externalization and also to understand whether it is due to physiological apoptosis or nonspecific necrosis. In this study DU‐145 cells were treated with these conjugates for 48 h at 0.5 and 1 μM concentrations.…”