ABSTRACT
In an effort to combine the anti-proliferative effect of CUR-BF2 and CUR compounds with anti-inflammatory benefits of non-steroidal anti-inflammatory drugs (NSAIDs), a library of the bis- and mono-NSAID/CUR-BF2 and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxy-benzaldehydes via an ester linkage, and by subsequent reaction with acetylacetone-BF2 to form the bis- and the mono-NSAID/CUR-BF2 adducts. Since conversion to NSAID/CUR by the previously developed decomplexation protocol showed limited success, a set of NSAID/CUR conjugates were independently prepared by directly coupling the NSAIDs with parent curcumin. The bis-NSAID/CUR-BF2 and bis-NSAID-CUR hybrids exhibited low cytotoxicity in NCI-60 assay, and in independent cell viability assay on colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, CaCo2) and in normal CR cells (CCD841CoN). By contrast, the mono-naproxin and mono-flurbiprofen CUR-BF2 adducts exhibited remarkable anti-proliferative and apoptopic activity in NCI-60 assay most notably against HCT-116 (colon), OVCAR-3 (ovarian), and ACHN (renal) cells. Computational molecular docking calculations showed favorable binding energies to HER2, VEGFR2, BRAF, and Bcl-2 as well as to COX-1 and COX-2, which in several cases exceeded known inhibitors. The main interactions between the ligands and the proteins were hydrophobic, although several hydrogen bonds were also observed. A sub-set of six compounds that had exhibited little or no cytotoxicity were tested for their anti-inflammatory response with THP-1 human macrophages in comparison to parent NSAIDs or parent curcumin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Curcumin/analogs & derivatives , Curcumin/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Line, Tumor , Curcumin/metabolism , Drug Screening Assays, Antitumor , Humans , Macrophages/drug effects , Molecular Docking Simulation , Protein Binding , Proteins/metabolismABSTRACT
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 inâ 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.
Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Density Functional Theory , Diarylheptanoids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms/pathology , Crystallography, X-Ray , Diarylheptanoids/chemical synthesis , Diarylheptanoids/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
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).
