Enhancement of cancer-cell-selective cytotoxicity by a dicopper complex with a phenanthrene amide-tether ligand conjugate <i>via</i> mitochondrial apoptosis

Hata, Machi; Saito, Ikue; Kadoya, Yuki; Tanaka, Yoshiki; Hitomi, Yutaka; Kodera, Masahito

doi:10.1039/d1dt02868e

Cited by 4 publications

(13 citation statements)

References 41 publications

(54 reference statements)

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“…The isolated solid was purified by recrystallization from MeOH/Et 2 O. The synthetic details, elemental analysis, electronic absorption, IR, and ESI MS data of HL X and 1 X are shown in Experimental Section and the Supporting Information, except for HL P2 and 1 P2 reported previously. , …”

Section: Resultsmentioning

confidence: 99%

“…) are formed from 1 and 1 P2 upon reaction with H 2 O 2 to accelerate the DNA cleavage and identified by the resonance Raman, cold-spray ionization (CSI) MS, and electronic absorption spectra. 17,18 In this study, μ-1,1-hydroperoxo complexes [Cu 2 (μ-O 2 H)-(L X )] 2+ (2 X , X = P1 and P3) (Scheme 3) are identified by the electronic absorption (Figure S8) and CSI MS spectra (Figures S9−S12). The electronic absorption spectra of 2 P1 and 2 P3 in MeCN at −30 °C show two bands at 340 (ε = 5800) and 400 (ε = 3100) nm and at 340 (ε = 5600) and 400 (ε = 3200 M −1 cm −1 ) nm, respectively.…”

Section: Spectroscopic Identification Of μ-11-hydroperoxo Complexes P...mentioning

confidence: 85%

“…The synthetic details, elemental analysis, electronic absorption, IR, and ESI MS data of HL X and 1 X are shown in Experimental Section and the Supporting Information, except for HL P2 and 1 P2 reported previously. 17,18 Structures of Dicopper Complexes 1 X . Structures of [Cu 2 (μ-OH)(L X )](ClO 4 ) 2 (1 X ) were examined by the electronic absorption spectra in Figure S1 were previously reported.…”

Section: S P E C T R O S C O P I C I D E N T I Fi C a T I O N O F μ -...mentioning

confidence: 99%

“…Moreover, 1 P2 exerted relatively high cancer cell-selective cytotoxicity. The caspase activity assay and intracellular visualization of 1 P2 by the phenathrenyl group as a fluorescent probe revealed that mitochondrial apoptosis plays a key role in cancer cell-selective cytotoxicity by 1 P2 . In this stage, however, the systematic design of DNA target/ligand conjugates has not been addressed to optimize cancer cell-selective cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates

et al. 2023

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The DNA target/ligand conjugates (HLX, X = Pn and Mn, n = 1–3) were synthesized where various lengths of −CONH(CH2CH2O) n CH2CH2NHCO– linkers with a 9-phenanthrenyl (P) or methyl (M) terminal as DNA targets replace the methyl group of 2,6-di(amide-tether cyclen)-p-cresol ligand (HL). DNA binding, DNA cleavage, cellular uptake, and cytotoxicity of [Cu2(μ-OH)(LX)](ClO4)2 (1X ) are examined and compared with those of [Cu2(μ-OH)(L)](ClO4)2 (1) to clarify roles of DNA targets. Upon reaction of 1X with H2O2, μ-1,1-O2H complexes are formed for DNA cleavage. 1P1 , 1P2 , and 1P3 are 22-, 11-, 3-fold more active for conversion of Form II to III in the cleavage of supercoiled plasmid DNA with H2O2 than 1, where the short P-linker may fix a dicopper moiety within a small number of base pairs to facilitate DNA double-strand breaks (dsb). This enhances the proapoptotic activity of 1P1 , 1P2 , and 1P3 , which are 30-, 12-, and 9.9-fold cytotoxic against HeLa cells than 1. DNA dsb and cytotoxicity are 44% correlated in 1P1–3 but 5% in 1M1–3 , suggesting specific DNA binding of P-linkers and nonspecific binding of M-linkers in biological cells. 1P1–3 exert cancer cell-selective cytotoxicity against lung and pancreas cancer and normal cells where the short P-linker enhances the selectivity, but 1M1–3 do not. Intracellular visualization, apoptosis assay, and caspase activity assay clarify mitochondrial apoptosis caused by 1P1–3 . The highest cancer cell selectivity of 1P1 may be enabled by the short P-linker promoting dsb of mitochondrial DNA with H2O2 increased by mitochondrial dysfunction in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Spectroscopic Identification Of μ-11-hydroperoxo Complexes P...mentioning

confidence: 85%

Section: S P E C T R O S C O P I C I D E N T I Fi C a T I O N O F μ -...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates

et al. 2023

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“…Cyclen (i.e., 1,4,7,10-tetraazacyclododecane) and its derivatives exhibit strong binding ability for various metal centres, and thus, such derivatives are extensively employed in DNA binding and cleavage processes. [83][84][85][86] Recently, Cu-dependent oxidative DNA cleavage by cyclen and its hetero-atom derivatives was studied by Kulak and co-workers. The order for DNA cleaving ability of the complexes was observed as oxacyclen (X = O) > sulfur analogue (X = S) > cyclen itself (X = NH).…”

Section: Cyclen Derivatives As Selfactivating Chemical Nucleasesmentioning

confidence: 99%

Transition metal complexes as self-activating chemical nucleases: proficient DNA cleavage without any exogenous redox agents

Kumar¹,

Tomar²,

Kumar

et al. 2023

Dalton Trans.

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Sm(Ⅲ), Gd(Ⅲ), and Eu(Ⅲ) complexes with 8‐hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI‐H460 cells

Yang,

Li,

et al. 2024

Drug Development Research

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Four lanthanide complexes with 8‐hydroxyquinoline‐2‐aldehyde‐2‐hydrazinopyridine (H‐L1), 8‐hydroxyquinoline‐2‐aldehyde‐2‐hydrazimidazole (H‐L2): [Sm(L1)2][Sm(L1)(NO3)3]·CHCl3·2CH3OH (1), [Gd(L1)2][Gd(L1)(NO3)3]·CHCl3·2CH3OH (2), [Sm(L2)(NO3)2]2·CH3OH (3), and [Eu(L2)(NO3)2]2·CH3OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI‐H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI‐H460 cells in G1 phase and induced mitochondria‐mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis‐related proteins and activated the caspase‐3/9 in NCI‐H460 cells. Therefore, complex 1 is a potential anticancer agent.

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Enhancement of cancer-cell-selective cytotoxicity by a dicopper complex with a phenanthrene amide-tether ligand conjugate via mitochondrial apoptosis

Abstract: Dicopper complexes [Cu2(μ-OH)(Ln)](ClO4)2 [n = 1 (1) and 2 (2)] with a novel phenanthrene amide-tether ligand conjugate (HL1) and the original p-cresol-2,6-bis(amidecyclen) (HL2) were synthesized. A phenanthrene unit of 1...

Cited by 4 publications

References 41 publications

Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates

Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates

Transition metal complexes as self-activating chemical nucleases: proficient DNA cleavage without any exogenous redox agents

Sm(Ⅲ), Gd(Ⅲ), and Eu(Ⅲ) complexes with 8‐hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI‐H460 cells

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