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Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)2] motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe–NO bonding interaction and of the delivery of NO+/•NO/HNO/NO– by the supporting ligands and nuclearity evolves into the “redesign of the natural [Fe(NO)2] motif” as a strategy to develop DNICs for NO-related biomedical application and ...

Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)

The synthesis of iron(II), cobalt(II) and nickel(II) complexes supported by chelating borate ligands containing one pyrazole and two thioethers, phenyl(pyrazolyl)bis((alkylthio)methyl)borates, [Ph(pz)BtR], is described. The six-coordinate complexes [Ph(pz)Bt]2M, M = Fe (1Fe), Co (1Co) and Ni (1Ni), form exclusively the cis isomers as confirmed by X-ray diffraction analyses. Whereas 1Co and 1Ni are high spin, 1Fe exhibits a room temperature magnetic moment, μeff = 4.1 μB, consistent with spin-crossover behavior. Quantitative analysis of the electronic spectrum of 2Ni leads to a value of Dq = 1086 cm−1, reflective of a ligand field strength somewhat weaker than those imposed by the related tridentate borate ligands Tp or PhTt. Replacement of the methylthioether substituent with the sterically more demanding tert-butylthioether leads to the isolation of [Ph(pz)BttBu]MX, M = Co, X = Cl (2Co); M = Ni, X = Cl (2Ni) or acac (3). The solid state structures of 2Co and 2Ni are chloride-bridged dimers. Additional high-spin cobalt(II) complexes, accessible under distinct preparative conditions, [κ2-Ph(pzH)BttBu] CoCl2·THF (4) and [κ2-Ph(pz)BttBu]2Co (5), have been fully characterized.

HSCH2CONHCH3 and HSCH2CON(CH3)2 containing a peptide bond are prepared for the synthesis of DNICs with/without intra-molecular hydrogen bonding, respectively. The IR ν(NO) bands of [(NO)2Fe(SCH2CONHCH3)2]− (2) appears at 1751, 1700 cm−1. In complex 2, the presence of intramolecular [NH⋯S] hydrogen bonding was verified by the observation of IR spectroscopy with N−H stretching frequency 3334 cm−1 (CDCl3) and subsequently confirmed by single-crystal X-ray diffraction showing N−S distance of 2.94 A. Complex 2 displays the rhombic EPR spectrum with g1 = 2.039, g2 = 2.031 and g3 = 2.013 at in frozen H2O. Complexes 2 and 3 rapidly release NO when exposed to light. The time needed for photolysis reactions of 2 is two times faster than that of 3 in less polar solvent. Representative time courses for the photolability of 2 and 3 in THF display the NO-off ability: 2 > 3.

Nitrosylation of the biomimetic reduced- and oxidized-form rubredoxin [Fe(SR)4]2-/1- (R = Ph, Et) in a 1:1 stoichiometry led to the formation of the extremely air- and light-sensitive mononitrosyl ...

Dinitrosyl iron complex [(−SC7H4SN)2Fe(NO)2]- (1) was prepared by reaction of [S5Fe(NO)2]- and bis(2-benzothiozolyl) disulfide. In synthesis of the analogous dinitrosyl iron compounds (DNICs), the stronger electron-donating thiolates [RS]- (R = C6H4-o-NHCOCH3, C4H3S, C6H4NH2, Ph), compared to [−SC7H4SN]- of complex 1, trigger thiolate-ligand substitution to yield [(−SC6H4-o-NHCOCH3)2Fe(NO)2]- (2), [(−SC4H3S)2Fe(NO)2]- (3), and [(SPh)2Fe(NO)2]- (4), respectively. At 298 K, complexes 2 and 3 exhibit a well-resolved five-line EPR signal at g = 2.038 and 2.027, respectively, the characteristic g value of DNICs. The magnetic susceptibility fit indicates that the resonance hybrid of {Fe+(•NO)2}9 and {Fe-(+NO)2}9 in 2 is dynamic by temperature. The IR νNO stretching frequencies (ranging from (1766, 1716) to (1737, 1693) cm-1 (THF)) of complexes 1−4 signal the entire window of possible electronic configurations for such stable and isolable {Fe(NO)2}9 [(RS)2Fe(NO)2]-. The NO-releasing ability of {Fe(NO)2}9 [(RS)2F...

Coordinative addition of [Mn(CO)5]- to TeCl4 resulted in the formation of a discrete chlorotellurate, [Cl4Te-Mn(CO)5]-. The X-ray crystal structure revealed the planar TeCl4 unit to be parallel to the Mn(CO)4 plane with the inert pair at Te in a trans position to the Mn(CO)ax.

The cis-[Mn(CO)4(TePh)2]−, similar to bidentate ligand PhTe(CH2)3TePh, acts as a “chelating metalloligand” for the synthesis of metallic tellurolate compounds. The reaction of cis[Mn(CO)4(TePh)2]− with BrMn(CO)5 in THF leads to a mixture of products[(CO)3,BrMn(μ-TePh)2Mn(CO)4]− (1) and Mn2(μ-TePh)2(CO)g (2). Complex 1 crystallizes in the triclinic space group Pl with a = 11.309(3) A, b = 14.780(5) A, c = 19.212(6) A, a = 76.05(3)° β = 72.31(3)°, γ = 70.41(3)° V = 2848(2) A3, Z = 2. Final R = 0.034 and Rw = 0.035 resulting from refinement of 10021 total reflections with 677 parameters, Dropwise addition of (MeTe)2 to a solution of [Me3O][BF4] in CH3CN leads to formation of [Me2TeTeMe][BF4], a potential MeTe+ donor ligand. In contrast to oxidative addition of diphenyl ditelluride to [Mn(CO)s]− to give cis-[Mn(CO)4(TePh)2]− which was thermally transformed into [(CO)3Mn(μ-TePh)3Mn(CO)3]−, reaction of [Mn(CO)5]−with [Me2TeTeMe]+ proceeded to give the monomeric species MeTeMn(CO)5 as initial product which was then dimerized into Mn2(μ-TeMe)2(CO)g (4).

Combination therapy aims to improve the pharmaceutical efficacy of different drugs, thus lowering the dosages used and reducing the side effects. However, interactions between individual drugs may also occur and lead to uncertain consequences. This study demonstrated that curcumin, a natural phenolic compound found in the rhizomes of turmeric, could either inhibit or enhance DNA cleavage caused by the synthetic nitrosyl-iron complex NC10 ([Fe₂(C₂H₅OS)₂(NO)₄]). Without UV irradiation, higher concentrations of curcumin protected DNA from being cleaved by NC10. Conversely, in the presence of lower concentrations of curcumin (< 5 µM), cleaved DNA increased by raising curcumin concentrations. After UV irradiation, the DNA protective effect of curcumin decreased while the enhancing DNA cleavage effect of curcumin remained. UV/visible spectroscopy analysis showed that curcumin is associated with the iron of NC10, suggesting the formation of curcumin-Fe complexes. Furthermore, a cytotoxicity assay revealed that cotreatment of NC10 and curcumin had synergetic effects on the growth inhibition of mouse melanoma B16-F10 cells. To our knowledge, this is the first study of the cotreatment of curcumin with inorganic compounds that showed synergistic cytotoxicity.

Anionic iron(0) tetracarbonyl with terminal phenyltellurolate ligand PhTe−, [PhTeFe(CO)4]−, has been synthesized and characterized. The title compound was obtained by addition of (PhTe)2 to [PPN][HFe(CO)4] THF solution dropwise. [PPN][PhTeFe(CO)4] crystallizes in the monoclinic space group C c, with a = 16.119(4) A, b = 13.141(3) A, c = 19.880(8) A, β = 93.04(3)°, V = 4205(2) A3, and Z = 4. The [PhTeFe(CO)4]− anion is a trigonal-bipyramidal complex in which the phenyltellurolate ligand occupies an axial position with Fe-Te bond length 2.630(5) A and the Fe-Te-C(Ph) angle is 103.4(5)°. The neutral iron(0)-telluroether compound, (PhTeMe)Fe(CO)4, was prepared by alkylation of the [PhTeFe(CO)4]−. Protonation of [PhTeFe(CO)4]−and reaction of H2Fe(CO)4 and PhTe)2 ultimately lead to formation of the known dimer Fe2(μ-TePh)2(CO)6 and H2.

The title complex, [Fe(2)(C(2)H(5)OS)(2)(NO)(4)], lies on a crystallographic inversion center. The Fe-Fe distance is characteristic of a metal-metal bond. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link complex mol-ecules into a two-dimensional network.

The water-soluble Roussin's red ester [(NO)(2)Fe(mu-SCH(2)CH(2)P(O)(CH(2)OH)(2))(2)Fe(NO)(2)] (1), a potential photochemical prodrug of an NO precursor, was synthesized from the reaction of HSCH(2)CH(2)P(O)(CH(2)OH)(2) (F) and [Fe(CO)(2)(NO)(2)]. The IR v(NO) stretching frequencies of complex 1 appear at 1759 (s), 1784 (s) and 1816 (w) cm(-1) in buffer (pH = 7.4). NO was released with a stoichiometry ratio Delta[NO]/Delta[1] = 3.6 +/- 0.2 when complex 1 was exposed to UV in deaerated aqueous phosphate buffer solution. Here light acts as an On/Off switch for NO release. Incubation of pBR322 supercoiled DNA with complex 1, followed by irradiation, produced DNA strand breakage. In contrast to the addition of carboxy-PTIO (NO radical scavenger), DNA strand breakage was not inhibited when the scavengers of hydroxyl radical and singlet oxygen were added. Complex 1 irradiated under a N(2) atmosphere exhibited the same cleavage efficiency as complex 1 irradiated under air. The results show that DNA strand cleavage efficiency depends on the concentration of complex 1, the pH value of the buffer, and the duration of the photolysis of complex 1. The conversion rate from supercoiled (SC form) to nicked circular (NC form) of complex 1 was 2.96 x 10(-2) s(-1). The results of a T4 ligase enzymatic assay reveals the nonhydrolytic DNA breakage mechanism. The NO-release ability of complexes 1, 2, and 3 follows the order 123. Upon UV-irradiation, complex 1 exhibits cytotoxicity against B16-F10 mouse melanoma cells.

Dinitrosyl iron complex [(-SC(7)H(4)SN)(2)Fe(NO)(2)](-) (1) was prepared by reaction of [S(5)Fe(NO)(2)](-) and bis(2-benzothiozolyl) disulfide. In synthesis of the analogous dinitrosyl iron compounds (DNICs), the stronger electron-donating thiolates [RS](-) (R = C(6)H(4)-o-NHCOCH(3), C(4)H(3)S, C(6)H(4)NH(2), Ph), compared to [-SC(7)H(4)SN](-) of complex 1, trigger thiolate-ligand substitution to yield [(-SC(6)H(4)-o-NHCOCH(3))(2)Fe(NO)(2)](-) (2), [(-SC(4)H(3)S)(2)Fe(NO)(2)](-) (3), and [(SPh)(2)Fe(NO)(2)](-) (4), respectively. At 298 K, complexes 2 and 3 exhibit a well-resolved five-line EPR signal at g = 2.038 and 2.027, respectively, the characteristic g value of DNICs. The magnetic susceptibility fit indicates that the resonance hybrid of {Fe(+)((*)NO)(2)}(9) and {Fe(-)((+)NO)(2)}(9) in 2 is dynamic by temperature. The IR nu(NO) stretching frequencies (ranging from (1766, 1716) to (1737, 1693) cm(-)(1) (THF)) of complexes 1-4 signal the entire window of possible electronic configurations for such stable and isolable {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-). The NO-releasing ability of {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) is finely tuned by the coordinated thiolate ligands. The less electron-donating thiolate ligands coordinated to {Fe(NO)(2)}(9) motif act as better NO-donor DNICs in the presence of NO-trapping agent [Fe(S,S-C(6)H(4))(2)](2)(2-). Interconversion between {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) and {Fe(NO)(2)}(10) [(Ph(3)P)(2)Fe(NO)(2)] was verified in the reaction of (a) [(RS)(2)Fe(NO)(2)](-), 10 equiv of PPh(3) and sodium-biphenyl, and (b) 2 equiv of thiol, [RS](-), and [(Ph(3)P)(2)Fe(NO)(2)], respectively. The biomimetic reaction cycle, transformation between {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) and {Fe(NO)(2)}(9) [(R'S)(2)Fe(NO)(2)](-), reversible interconversion of {Fe(NO)(2)}(9) and {Fe(NO)(2)}(10) DNICs, and degradation/reassembly of [2Fe-2S] clusters may decipher and predict the biological cycle of interconversion of {Fe(NO)(2)}(9) DNICs, {Fe(NO)(2)}(10) DNICs, and the [Fe-S] clusters in proteins.

A series of mononuclear zinc thiolate complexes have been prepared and fully characterized. The reactions of the complexes with alkyl halides, leading to zinc halides and the corresponding thioethers, have been examined by kinetic methods. In toluene, the reactions obey a second-order rate law displaying activation parameters consistent with a S N 2 attack of the zinc-bound thiolate on the carbon electrophile. Intramolecular hydrogen bonding of an amide N—H to the thiolate sulfur reduces the nucleophilicity and consequently, the rate of alkylation more than 30-fold at 25°C. The H-bonding shows an inverse H/D isotope effect of 0.33 (60°C) ascribed to differential H-bonding for the two isotopomers due to zero point energy differences. These model studies provide quantitative evaluation of H-bonding on reaction rates relevant to zinc thiol-activating proteins.

The syntheses and molecular structures of a series of tetrahedral zinc complexes designed to model the active sites in Escherichia coli methionine synthases are reported. [PhTttBu]ZnBr (PhTttBu = phenyltris((tert-butylthio)-methyl)borate) was prepared and characterized crystallographically to provide entry into [S3]ZnX complexes. Metathesis with KSPh yielded the phenylthiolato complex, [PhTttBu]Zn(SPh), which represents a structural mimic of the homocysteine ligated form of the enzyme. Alternatively, [S2N]ZnX (X = Br, CH3, SPh) species were prepared using the new mixed-donor ligands, [Ph(pz)BttBu] (phenyl(pyrazolyl)bis((tert-butylthio)methyl)borate) and [Ph(pztBu)BttBu] (phenyl(3-tert-butylpyrazolyl)bis((tert- butylthio)methyl)borate). Protonolysis of [Ph(pztBu)-BttBu]Zn(CH3) by PhSH in toluene yielded [Ph(pztBu)BttBu]Zn(SPh), a synthetic analogue of the homocysteine ligated form of cobalamin-independent methionine synthase (Met E). The average Zn-S bond distance in [Ph-(pztBu)BttBu]Zn(SPh) of 2.37 A compares well with the EXAFS-derived distance of 2.31 A found in the homocysteine-bound form of Met E.

Two new borate ligands, PhB(CH2SCH3)2(pz)– (1–) and Ph2B(CH2SCH3)(pz)– (2–) (pz = 1-pyrazolyl), have been prepared to provide mixed donor sets, ‘NS2’ and ‘NS’, respectively, to transition metal ions.