Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer

Pancreatic cancer is the most lethal malignancy of the gastrointestinal tract. Due to its propensity for early local and distant spread, affected patients possess extremely poor prognosis. Currently applied treatments are not effective enough to eradicate all cancer cells, and minimize their migration. Besides, these treatments are associated with adverse effects on normal cells and organs. These therapies are not able to increase the overall survival rate of patients; hence, finding novel adjuvants or alternatives is so essential. Up to now, medicinal herbs were utilized for therapeutic goals. Herbal-based medicine, as traditional biotherapeutics, were employed for cancer treatment. Of them, apigenin, as a bioactive flavonoid that possesses numerous biological properties (e.g., anti-inflammatory and anti-oxidant effects), has shown substantial anticancer activity. It seems that apigenin is capable of suppressing the proliferation of cancer cells via the induction of cell cycle arrest and apoptosis. Besides, apigenin inhibits metastasis via down-regulation of matrix metalloproteinases and the Akt signaling pathway. In pancreatic cancer cells, apigenin sensitizes cells in chemotherapy, and affects molecular pathways such as the hypoxia inducible factor (HIF), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1). Herein, the biotherapeutic activity of apigenin and its mechanisms toward cancer cells are presented in the current review to shed some light on anti-tumor activity of apigenin in different cancers, with an emphasis on pancreatic cancer. © Copyright © 2020 Ashrafizadeh, Bakhoda, Bahmanpour, Ilkhani, Zarrabi, Makvandi, Khan, Mazaheri, Darvish and Mirzaei

Uncovering a copper(II) Alkynyl Complex in C−C Bond Forming Reactions

Copper(II) alkynyl species are proposed as key intermediates in numerous Cu−catalysed C−C coupling reactions. Supported by a β−diketiminate ligand, the three coordinate copper(II) alkynyl [CuII]−C≡CAr (Ar = 2,6−Cl2C6H3) forms upon reaction of the alkyne H−C≡CAr with the copper(II) tert−butoxide complex [CuII]−OtBu. In solution, this [CuII]−C≡CAr species cleanly transforms the to the Glaser coupling product ArC≡C−C≡CAr and [CuI](solvent). Addition of nucleophiles R′C≡CLi (R′ = aryl, silyl) and Ph–Li to [CuII]−C≡CAr affords the corresponding Csp−Csp and Csp−Csp2coupled products RC≡C−C≡CAr and Ph–C≡CAr with concomitant generation of [CuI](solvent) and {[CuI]−C≡CAr}−. Supported by DFT calculations, redox disproportionation forms [CuIII](C≡CAr)(R) species that reductively eliminate R−C≡CAr products. [CuII]−C≡CAr also captures the trityl radical Ph3C• to give Ph3C−C≡CAr. Radical capture represents the key Csp−Csp3 bond forming step in the copper catalysed C-H functionalization of benzylic substrates R−H with alkynes H−C≡CR′ (R′ = (hetero)aryl, silyl) that provide Csp−Csp3 coupled products R−C≡CR via radical relay with tBuOOtBu as oxidant.</p

Copper(II) Ketimides in sp3 C-H Amination

Commercialy available benzphenone imine (HN=CPh2) reacts with b-diketiminato copper(II) tert-butoxide complexes [CuII]-OtBu to form isolable copper(II) ketimides [CuII]-N=CPh2. Structural characterization of the three coordinate copper(II) ketimide [Me3NN]Cu-N=CPh2 reveals a short Cu-Nketimide distance (1.700(2) Å) with a nearly linear Cu-N-C linkage (178.9(2)°). Copper(II) ketimides [CuII]-N=CPh2 readily capture alkyl radicals R• (PhCH(•)Me and Cy•) to form the corresponding R-N=CPh2 products that competes with N-N coupling of copper(II) ketimides [CuII]-N=CPh2 to form the azine Ph2C=N-N=CPh2. Copper(II) ketimides [CuII]-N=CAr2 serve as intermediates in catalytic sp3 C-H amination of substrates R-H with ketimines HN=CAr2 and tBuOOtBu as oxidant to form N-alkyl ketimines R-N=CAr2. This protocol enables the use of unactivated sp3 C-H bonds to give R-N=CAr2 products easily converted to primary amines R-NH2 via simple acidic deprotection.</p

Radical Capture at Ni(II) Complexes: C-C, C-N, and C-O Bond Formation

The dinuclear b-diketiminato NiIItert-butoxide {[Me3NN]Ni}2(μ-OtBu)2 (2), synthesized from [Me3NN]Ni(2,4-lutidine) (1) and di-tert-butylperoxide, is a versatile precursor for the synthesis of a series of NiIIcomplexes [Me3NN]Ni-FG to illustrate C-C, C-N, and C-O bond formation at NiII via radicals. {[Me3NN]Ni}2(μ-OtBu)2 reacts with nitromethane, alkyl and aryl amines, acetophenone, benzamide, ammonia and phenols to deliver corresponding mono- or dinuclear [Me3NN]Ni-FG species (FG = O2NCH2, R-NH, ArNH, PhC(O)NH, PhC(O)CH2, NH2and OAr). Many of these NiII complexes are capable of capturing the benzylic radical PhCH(•)CH3 to deliver corresponding PhCH(FG)CH3 products featuring C-C, C-N or C-O bonds. DFT studies shed light on the mechanism of these transformations and suggest two competing pathways that depend on the nature of the functional groups. These radical capture reactions at [NiII]-FG complexes outline key C-C, C-N, and C-O bond forming steps and suggest new families of nickel radical relay catalysts.</p

Lewis Acid Coordination Redirects S-Nitrosothiol Reduction

S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for nitric oxide in biology and are responsible for a myriad of physiological responses. While copper enzymes promote NO release from RSNOs by serving as Lewis acids capable of intramolecular electron-transfer, redox innocent Lewis acids separate these two functions to reveal the effect of coordination on structure and reactivity. The synthetic Lewis acid B(C6F5)3 coordinates to the RSNO oxygen atom in adducts RSNO-B(C6F5)3, leading to profound changes in the RSNO electronic structure and reactivity. Although RSNOs possess relatively negative reduction potentials (-1.0 to -1.1 vs. NHE), B(C6F5)3 coordination increases their reduction potential by over 1 V into the physiologically accessible +0.1 V vs. NHE. Outer-sphere chemical reduction results in formation of the Lewis acid stabilized hyponitrite dianion trans-[LA–O–N=N–O–LA]2– (LA = B(C6F5)3) that releases N2O upon acidification. Mechanistic and computational studies support initial reduction to the [RSNO-B(C6F5)3]•/- radical-anion susceptible to N-N coupling prior to loss of RSSR