Synthesis and pharmacological characterization of glucopyranosyl-conjugated benzyl derivatives as novel selective cytotoxic agents against colon cancer

Abstract

Glucopyranosyl-conjugated benzyl derivatives containing a [1,2,3]-triazole linker were synthesized. Benzyl served as an important pharmacophore in anti-cancer compounds. Compound 8d inhibited the proliferation of colorectal cancer cells with the potency comparable to 5-fluorouracil (5-FU) with improved selectivity towards cancer cells. The antiproliferative activity of 8d is achieved through triggering apoptotic cell death.

Keywords: 293T; HCT-116; colon cancer; glucopyanosyl-conjugated benzyl.

Scheme 1.

Some representative compounds with benzyl group (in blue) as pharmacophore.

Scheme 2.

Synthesis of glucopyranosyl-conjugated benzyl derivatives. Reaction conditions: (a) 2, K₂CO₃, MeOH, rt; (b) pyridine, Ac₂O; (c) NaH, THF; (d) 4, sodium ascorbate, copper sulfate pentahydrate, microwave, 100°C, N, N-dimethylforamide; (e) MeOH, water and NEt₃ (the ratio of volume is 5 : 4 : 1), reflux, 4 h.

Figure 1.

Compound 8d inhibits the proliferation of HCT-116 cells. (a) Representative sections of compound 8d-treated HCT-116 cells showing confluence area detected by Incucyte system. (b) Quantitative data of HCT-116 cell confluence by confluence area calculated module in Incucyte system. (c) Representative wells of HCT-116 clones treated with or without compound 8d. (d) Colony number was quantified in the imaging sections by ImageJ. (*p < 0.05, **p < 0.001 and ***p < 0.0001 versus control.)

Figure 2.

Compound 8d induces apoptotic cell death in HCT-116 cells. (a) Representative nuclear morphometry stained with Hoechst 33258 in HCT-116 cells treated with or without compound 8d for 48 and 72 h; the scale bar represents 10 μm, ×400 magnification. (b) Representative TUNEL staining in HCT-116 cells treated with or without compound 8d for 72 h; the scale bar represents 10 µm, ×400 magnification. (c) Representative Annexin V-FITC staining in HCT-116 cells treated with compound 8d for 72 h; the scale bar represents 10 µm, ×400 magnification. (d) The rate of apoptotic death cells after compound 8d treatment was quantified by the Annexin V/PI assay.