Synthesis, Computational Docking Study, and Biological Evaluation of a Library of Heterocyclic Curcuminoids with Remarkable Antitumor Activity. (5th August 2018)

• Record Type: Journal Article
• Authors: Laali, Kenneth K.; Greves, William J.; Zwarycz, Angela T.; Correa Smits, Sebastian J.; Troendle, Frederick J.; Borosky, Gabriela L.; Akhtar, Sharoon; Manna, Alak; Paulus, Aneel; Chanan‐Khan, Asher; Nukaya, Manabu; Kennedy, Gregory D.
• Is Part Of: ChemMedChem. Volume 13:Number 18(2018)
• Page Start: 1895
• Page End: 1908
• Publication Date: 2018-08-05
• Subjects: antitumor agents -- apoptosis -- binding affinity -- curcuminoids -- multiple myeloma; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800320
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF2 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–BF2 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 IC50 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). Abstract : Finding a CUR for cancer : A library of heterocyclic curcuminoids (CUR) based on indole, benzothiophene, and benzofuran were synthesized. Guided by favorable computational docking energies with HER2, proteasome, VEGFR, BRAF, and Bcl‐2, hit compounds were discovered among indole‐based CUR–BF2 adducts and their bis‐thiocyanato derivatives by in vitro assays against multiple myeloma and colorectal cancer cells, with significantly lower cytotoxicity toward normal cells.