Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer

Abstract

A series of deuterated curcuminoids (CUR) were synthesized, bearing two to six OCD3 groups, in some cases in combination with methoxy groups, and in others together with fluorine or chlorine atoms. A model ring‐deuterated hexamethoxy‐CUR–BF2 and its corresponding CUR compound were also synthesized from a 2,4,6‐trimethoxybenzaldehyde‐3,5‐d2 precursor. As with their protio analogues, the deuterated compounds were found to remain exclusively in the enolic form. The antiproliferative activities of these compounds were studied by in vitro bioassays against a panel of 60 cancer cell lines, and more specifically in human colorectal cancer (CRC) cells (HCT116, HT29, DLD‐1, RKO, SW837, and Caco2) and in normal colon cells (CCD841CoN). The deuterated CUR–BF2 adducts exhibited better overall growth inhibition by NCI‐60 assay, while for other CUR–BF2 adducts the non‐deuterated analogues were more cytotoxic. Results of the more focused comparative cell viability assays followed the same trend, but with some variation depending on cell lines. The CUR–BF2 adducts exhibited significantly higher cytotoxicity than CURs. Structural studies (X‐ray and DFT) and computational molecular docking calculations comparing their inhibitory efficacy with those of known anticancer agents used in chemotherapy are also reported.

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

“…Variously substituted hydroxybenzaldehydes were coupled to flufenamic acid, flurbiprofen, indomethacin, naproxen, and ibuprofen using classical Steglich esterification protocol, employing DCC/DMAP, and the coupling adducts were obtained in good to excellent isolated yields. These were then reacted with acetylacetone-BF 2 complex (Scheme 1) in 2 : 1 ratio, following previously established procedures, [11][12][13][14][15] to obtain the corresponding bis-NSAID/CUR-BF 2 adducts. Thermal decomplexation of the BF 2 adducts in the Monowave reactor [24] were successful in some cases depending on the NSAID, and from this simple route the corresponding bis-NSAID/CUR compounds were directly obtained (Scheme 1).…”

“…Binding energies in the active site of various proteins involved in carcinogenic processes were determined and compared with the binding affinities of their corresponding known inhibitors applied in anticancer therapies. The proteins selected for these docking studies are involved in diverse oncogenic pathways, which were described in previous works . In addition, the potential anti‐inflammatory activity of the CUR‐NSAID conjugates was evaluated by docking calculations in the active site of cyclooxygenase enzymes COX‐1 and COX‐2.…”

“…[11][12][13][14] Libraries of deuterated-CUR-BF 2 and CUR analogs were also synthesized and studied. [15] These strategies produced diverse libraries of "CUR-inspired" compounds, and in-vitro bioassay studies identified several potential "hit compounds" with high anti-proliferative and apoptotic efficacy, most notably in multiple myeloma and colorectal cancer (CRC) that warrant further studies. The CUR-BF 2 adducts of some of these compounds proved especially effective.…”

“…[9,10] Work from this laboratory has focused on structural modifications by tuning steric and electronic effects through introduction of activating and deactivating substitutents, introducing fluorinated moieties in an effort to improve lipophilicity and metabolic stability, synthesis of pyazole and isoxazole derivatives, and synthesis of libraries of CUR-inspired heterocyclic analogs. [11][12][13][14] Libraries of deuterated-CUR-BF 2 and CUR analogs were also synthesized and studied. [15] These strategies produced diverse libraries of "CUR-inspired" compounds, and in-vitro bioassay studies identified several potential "hit compounds" with high anti-proliferative and apoptotic efficacy, most notably in multiple myeloma and colorectal cancer (CRC) that warrant further studies.…”

“…Much work has been devoted to improving solubility, metabolic stability, lipophilicity, and other properties through synthesis of analogs, and these developments have been summarized in recent reviews . Work from this laboratory has focused on structural modifications by tuning steric and electronic effects through introduction of activating and deactivating substitutents, introducing fluorinated moieties in an effort to improve lipophilicity and metabolic stability, synthesis of pyazole and isoxazole derivatives, and synthesis of libraries of CUR‐inspired heterocyclic analogs . Libraries of deuterated‐CUR‐BF 2 and CUR analogs were also synthesized and studied .…”