Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity.

Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity.

European journal of medicinal chemistry (2012-10-10)

Rodrigo Abonia, Daniel Insuasty, Juan Castillo, Braulio Insuasty, Jairo Quiroga, Manuel Nogueras, Justo Cobo

ABSTRACT

Novel quinoline-2-one based chalcones were synthesized from a Claisen-Schmidt condensation by using the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI(50) values ≤1.0 μM, being the HCT-116 (Colon, GI(50) = 0.131 μM) and LOX IMVI (Melanoma, GI(50) = 0.134 μM) the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be used as lead compound for developing new anticancer agents.

MATERIALS

Product Number

Brand

Product Description

631833

Supelco

1,4-Dioxane solution, NMR reference standard, 5 mM in benzene-d₆ (99.6 atom % D), NMR tube size 3 mm × 8 in.

61699

Supelco

Potassium hydroxide concentrate, 0.1 M KOH in water (0.1N), Eluent concentrate for IC

704814

Sigma-Aldrich

1,4-Dioxane solution, NMR reference standard, 10 mM in D₂O ("100%", 99.96 atom % D), NMR tube size 5 mm × 7 in.

736171

Supelco

1,4-Dioxane solution, NMR reference standard, 40% in benzene-d₆ (99.6 atom % D), NMR tube size 5 mm × 8 in.

CRM48367

Supelco

1,4-Dioxane solution, certified reference material, 2000 μg/mL in methanol, ampule of 1 mL

631868

Supelco

1,4-Dioxane solution, NMR reference standard, 5 mM in chloroform-d (99.8 atom % D), NMR tube size 3 mm × 8 in.

551368

Sigma-Aldrich

1,4-Dioxane solution, NMR reference standard, 40% in benzene-d₆ (99.6 atom % D)

612073

Sigma-Aldrich

1,4-Dioxane solution, NMR reference standard, 40% in benzene-d₆ (99.6 atom % D), chromium(III) acetylacetonate 5 mg/mL, NMR tube size 3 mm × 8 in.

611905

Sigma-Aldrich

1,4-Dioxane solution, NMR reference standard, 40% in benzene-d₆ (99.6 atom % D), chromium(III) acetylacetonate 5 mg/mL, NMR tube size 5 mm × 8 in.

76887

Supelco

1,4-Dioxane, analytical standard

684228

Sigma-Aldrich

1,4-Dioxane solution, NMR reference standard, 40% in benzene-d₆ (99.6 atom % D), NMR tube size 10 mm × 8 in.

34857

Sigma-Aldrich

1,4-Dioxane, suitable for HPLC, ≥99.5%

360481

Sigma-Aldrich

1,4-Dioxane, ACS reagent, ≥99.0%, contains ≤25 ppm BHT as stabilizer

676934

Sigma-Aldrich

1,4-Dioxane, ACS reagent, ≥99.0%

60377

Sigma-Aldrich

Potassium hydroxide, tested according to Ph. Eur.

06103

Sigma-Aldrich

Potassium hydroxide, technical, ≥85%, powder

P1767

Sigma-Aldrich

Potassium hydroxide, ≥85% KOH basis, pellets, white

P5958

Sigma-Aldrich

Potassium hydroxide, BioXtra, ≥85% KOH basis

911062

Sigma-Aldrich

Potassium hydroxide, free-flowing, Redi-Dri^™, ACS reagent, ≥85%, pellets

484016

Sigma-Aldrich

Potassium hydroxide, reagent grade, 90%, flakes

P4494

Supelco

Potassium hydroxide solution, volumetric, 8.0 M KOH (8.0N)

221473

Sigma-Aldrich

Potassium hydroxide, ACS reagent, ≥85%, pellets

306568

Sigma-Aldrich

Potassium hydroxide, semiconductor grade, pellets, 99.99% trace metals basis (Purity excludes sodium content.)

417661

Sigma-Aldrich

Potassium hydroxide solution, 45 wt. % in H₂O