Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived by product (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5–1.0 µM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational research will guide us to develop a novel ω-6-based diet-care strategy in combination with current chemotherapy for colon cancer prevention and treatment.
A convenient and waste-free synthesis of indene-based tertiary carbinamines by rhodium-catalyzed imine/alkyne [3+2] annulation is described. Under the optimized conditions of 0.5-2.5 mol % [{(cod)Rh(OH)}(2)] (cod=1,5-cyclooctadiene) catalyst, 1,3-bis(diphenylphosphanyl)propane (DPPP) ligand, in toluene at 120 degrees C, N-unsubstituted aromatic ketimines and internal alkynes were coupled in a 1:1 ratio to form tertiary 1H-inden-1-amines in good yields and with high selectivities over isoquinoline products. A plausible catalytic cycle involves sequential imine-directed aromatic C-H bond activation, alkyne insertion, and a rare example of intramolecular ketimine insertion into a Rh(I)-alkenyl linkage.
The reaction of monomeric and dimeric rhodium(I) amido complexes with unactivated olefins to generate imines is reported. Transamination of {(PEt(3))(2)RhN(SiMePh(2))(2)} (1a) or its -N(SiMe(3))(2) analogue 1b with p-toluidine gave the dimeric [(PEt(3))(2)Rh(mu-NHAr)](2) (Ar = p-tolyl) (2a) in 80% isolated yield. Reaction of 2a with PEt(3) generated the monomeric (PEt(3))(3)Rh(NHAr) (Ar = p-tolyl) (3a). PEt(3)-ligated arylamides 2a and 3a reacted with styrene to transfer the amido group to the olefin and to form the ketimine Ph(Me)C=N(p-tol) (4a) in 48-95% yields. The dinuclear amido hydride (PEt(3))(4)Rh(2)(mu-NHAr)(mu-H) (Ar = p-tolyl) (5a) was formed from reaction of 2a in 95% yield, and a mixture of this dimeric species and the (PEt(3))(n)RhH complexes with n = 3 and 4 was formed from reaction of 3a in a combined 75% yield. Propene reacted with 2a to give Me(2)C=N(p-tol) (4b) and 5a in 90 and 57% yields. Propene also reacted with 3a to give 4b and 5a in 65 and 94% yields. Analogues of 2a and 3a with varied electronic properties also reacted with styrene to form the corresponding imines, and moderately faster rates were observed for reactions of electron-rich arylamides. Kinetic studies of the reaction of 3a with styrene were most consistent with formation of the imine by migratory insertion of olefin into the rhodium-amide bond to generate an aminoalkyl intermediate that undergoes beta-hydrogen elimination to generate a rhodium hydride and an enamine that tautomerizes to the imine.
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