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Optimization of a Series of Novel Chalcone Derivatives for Anti‐Cancer Activity
Author(s) -
Whited Tawna L.,
Stang Christopher R.T.,
Adams Bryce R.,
Khupse Rahul S.,
Dudley Richard W.,
Schneider Ryan A.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.515.3
Subject(s) - chalcone , pharmacophore , chemistry , cancer , cytotoxicity , apoptosis , cancer cell , cell culture , melanoma , blot , biochemistry , in vitro , cancer research , pharmacology , stereochemistry , biology , medicine , gene , genetics
Chalcones are natural products that have been studied for their numerous pharmacological properties including anti‐cancer, antioxidant, and anti‐inflammatory effects. An alpha‐beta unsaturated ketone at the core of the chalcone scaffold provides the basis for the multitude of pharmacological effects. However, synthetic modifications to the periphery of the scaffold seemingly afford diverse activity. We synthesized a small library of chalcone derivatives to screen for anti‐cancer activity in vitro . Additionally, we sought to determine the required pharmacophore and optimize structural features in order to improve activity. We previously reported preliminary data with two of these compounds, RK6 and RK7. Here we report our findings for two additional derivatives (RK8 and RK9) and compare them to the previous data for optimization of anti‐cancer activity. These four compounds were screened for anti‐cancer activity in multiple, diverse, human cancer cell lines (A375 melanoma, CRL‐1620 glioblastoma, HT‐29 colon carcinoma, and MCF‐7 breast adenocarcinoma). GI50 values for each of the compounds in all four cancer cell lines were determined using the CyQUANT® NF assay. Treatments were administered with increasing concentrations (1–100 μM) of each compound separately for 48 hours. RK6 and RK7 demonstrated activity in each of the four lines tested with GI50 values ranging from 16–48 μM. RK8 and RK9 showed activity in some, but not all cell lines, with GI50 values ranging from 36 to greater than 100 μM. A Caspase‐Glo® 3/7 assay and western blotting for cleaved caspases‐3/7 and cleaved poly(ADP‐ribose) polymerase were done to determine potential mechanisms of cancer cell death. Collectively, results from our experiments suggest that these chalcones induce cell death in a non‐caspase‐dependent manner. Additional studies are ongoing to optimize the chalcone scaffold and to determine the mechanisms of anti‐cancer activity.