In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR-BF adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR-BF and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).
The Front Cover shows the microscope slides of colorectal cancer cells (DLD‐1) treated with two new indole‐based heterocyclic curcuminoids bearing SCN substituents [3‐thiocyanato‐indole‐5‐curcuminoid–BF2 adduct (4‐BF2) on the left and (1E,4E,6E)‐5‐hydroxy‐1,7‐bis(3‐thiocyanoindole‐4)hepta‐1,4,6‐trien‐3‐one (5) on right] at 10 μM concentrations for 24 h. For comparison, the center slide shows cells treated with DMSO alone (control) for 24 h. Heterocyclic CUR‐BF2 compounds, such as indole‐4‐curcuminoid‐BF2 adduct (3‐BF2) shown in the center pose, exhibit favorable docking ability into Bcl‐2. Hydrophobic contacts between the atoms of the ligand and protein residues are the principle interactions involved, along with hydrogen bond interactions between F and N ligand atoms and hydrogen bond donor groups in neighboring protein residues. The DFT‐optimized structures of two remarkably active bis‐SCN‐substituted CUR‐BF2 compounds are displayed as well. Unlike the very distinct yellow color of curcumin itself, these new heterocyclic analogs have distinctly different colors. More information can be found in the Full Paper by Kenneth K. Laali et al. on page 1895 in Issue 18, 2018 (DOI: 10.1002/cmdc.201800320).
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