Synthesis of heterocycle based carboxymethyl cellulose conjugates as novel anticancer agents targeting HCT116, MCF7, PC3 and A549 cells

Abstract

Toward developing anticancer agents, heterocycle-based carboxymethyl cellulose conjugates have been synthesized. 2-Cyano-N'-(aryl/heteroarylethylidene)acetohydrazides and ethyl 2-cyano-3-(heteryl)acrylates were utilized as precursors for the synthesis of pyridine-based compounds. The chemical structures of the synthesized derivatives were characterized using various spectroscopic techniques, including ¹H-, ¹³C-NMR, Fourier transform infrared spectroscopy (FTIR), as well as scanning electron microscopy (SEM).The anticancer effects of compounds on HCT-116, MCF-7, PC3 and A549 cancer cell lines were investigated and their cytotoxicity against RPE-1 normal cells was estimated to determine their safety. Compounds 4b and 7c exhibit high selectivity toward cancer cells while maintaining a strong safety margin for normal cells. The results demonstrated that the novel heterocycle-based carboxymethyl cellulose conjugates are promising and can be further evaluated as a potential therapeutic agent.

Keywords: Anticancer; Carboxymethyl cellulose; Pyridine; Synthesis.

Fig. 1

Targeted anticancer agents containing pyridine scaffolds.

Fig. 2

Synthetic pathway for compounds 7a-d. Reagents and conditions: i) EtOH, reflux, 1 hour. ii) AcOH/MeOH (2:1), reflux, 3h.

Fig. 3

Suggested modifications of CMC with the synthesized compounds 4b & 7c.

Fig. 4

FTIR of CMC and composites.

Fig. 5

SEM of CMC and composites.

Fig. 6

XRD of CMC and composites.

Fig. 7

Effect of the synthesized compounds on HCT-116 Cell viability. The survival fraction of HCT-116 cells was assessed using the MTT assay after 48 h of treatment with varying concentrations of the synthesized compounds (6.25–100 µg/mL). Data are presented as mean ± SD from three independent experiments. *p < 0.01 compared to untreated cells.

Fig. 8

Effect of synthesized compounds on PC3 cells viability. Survival fraction evaluated using the MTT assay after 48 h of treatment with varying concentrations of compounds (6.25–100) µg/ml. Data are expressed as mean ± SD from three independent experiments. * p˂0.01 compared to untreated cells.

Fig. 9

Effect of synthesized compounds 4b and 7c on A549 cells viability. Survival fraction was evaluated using the MTT assay after 48 h of treatment with varying concentrations of compounds 4b and 7c (6.25–100 µg/mL). Data are expressed as mean ± SD from three independent experiments. * p˂0.01 compared to untreated cells.

Fig. 10

Effect of synthesized compounds on RPE-1 cells viability. The viability of RPE-1 cells was assessed using the MTT assay after 48 h of treatment with varying concentrations of the synthesized compounds (6.25–100 µg/mL). Data are expressed as mean ± SD from three independent experiments. *p < 0.01 compared to untreated cells.

Fig. 11

Effect of different compounds on the inhibition of nitric oxide production in LPS-stimulated RAW264.7 macrophages. RAW 264.7 macrophages were exposed to different compounds (100 µg/mL) along with LPS (1 µg/mL) or LPS alone for 24 h. Nitric oxide (NO) production was measured using the Griess reagent, and the results are expressed as mean ± SD (n = 3).