The water-soluble Roussin's red ester acting as a potential photochemical NO-delivery agent: Photolysis reactions, DNA cleavage and anticancer activity

Abstract

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 1 > 2 > 3. Upon UV-irradiation, complex 1 exhibits cytotoxicity against B16-F10 mouse melanoma cells.

Synergistic antitumor effect of curcumin and dinitrosyl iron complexes for against melanoma cells

“…We have reported NO released from DNICs and Roussin's red ester can kill cancer cell [47] and here pretreatment of NC03 and cotreatment of NC03 and curcumin did not show any synergistic cytotoxic effect may caused by the quenching of NO by curcumin, namely, pretreatment of curcumin exerts the anticancer effect followed by the NO released from NC03 to enhance the effect against the tumor cells. These results also suggest that NC03 may release NO outside the cells without directly interaction with curcumin.…”

New members of a class of dinitrosyliron complexes (DNICs): The characteristic EPR signal of the six-coordinate and five-coordinate {Fe(NO)2}9 DNICs

“…In spite of the tetrahedral {Fe(NO) 2 } 9 DNICs [(L) 2 Fe(NO) 2 ] − (L = thiolate, imidazolate) displaying EPR signal g = 2.03 [12][13][14][15][16][17][27][28][29], the distinct EPR signals exhibited by the squarepyramidal {Fe(NO) 2 } 9 DNIC [(6-Me 3 -TPA)Fe(NO) 2 ] + (g = 2.02) [25], the square-pyramidal {Fe(NO) 2 } 9 DNICs 2-iPr PDI (g = 2.015)/ 4-PyImiS (g = 2.018) and the six-coordinate {Fe(NO) 2 } 9 DNICs 1-TPA (g = 2.018)/[(1-MeIm) 2 (η 2 -ONO)Fe(NO) 2 ] (g = 2.013) [24] suggested that the EPR spectra in combination with IR ν NO spectra may serve as an efficient tool for the discrimination of the various geometrical {Fe(NO) 2 } 9 DNICs (Table 1) In the previous study on the reaction of {Fe(NO) 2 } 9 DNIC [(NO) 2 Fe(C 12 H 8 N) 2 ] − and incoming ligands ((S 2 CNMe 2 ) 2 , (PyPepS) 2 and P(C 6 H 3 -3-SiMe 3 -2-SH) 3 , respectively), the geometric structure and electronic structure of the intermediates dictating the release of [NO] + , ·NO and [NO] − , respectively, were demonstrated [12]. In this study, we further showed how the geometric structure of {Fe (NO) 9 DNICs, and modulated release of nitroxyl from DNICs. To our best knowledge, although no six-/fivecoordinate {Fe(NO) 2 } 9 DNIC was characterized in the biological study [1,38], the tendency of five-coordinate {Fe(NO) 2 } 9 DNICs to release nitroxyl may decipher that this type of DNICs derived from the classical {Fe(NO) 2 } 9 /{Fe(NO) 2 } 10 DNICs could be regarded as the storage/transport of nitroxyl regulated by the protein structure and charge of the immediate vicinity.…”

“…Presumably, the optimum electron-donating coordinated ligands tuning the optimum electronic structure of the {Fe(NO) 2 } core of DNICs affords the most stable {Fe(NO) 2 } 9 DNICs. These results may rationalize that most of the DNICs characterized and proposed nowadays are the four-coordinate {Fe(NO) 2 } 9 DNICs bound to the proteins almost through the thiolate groups of cysteinate/glutathione side chains in biological system [1][2][3][4][5][6][7][8][9][10][11].…”

“…DNICs were found to trigger the activation of cationic channels, inhibition of enzymes and apoptosis of Jurkat cells, although the NO-release mechanism of DNICs remained elusive [7,8]. Release of nitric oxide from irradiation of DNIC triggering the DNA strand breakage of pBR322 supercoiled DNA was reported [9]. Activation of vasodilation via nitrosylation of the heme center in sGC [10], stimulation of transcription through degradation of the [2Fe-2S] cluster of SoxR [8], and upregulation of heat shock protein 70 via protein S-nitrosylation by DNICs were demonstrated [11].…”

Chemistry of Nitrosyliron Complexes Supported by a β-Diketiminate Ligand

“…Much of this interest stems from the demonstration that DNICs can participate in a host of physiological processes normally mediated by NO gas 2-8. DNICs also hold promise as therapeutic delivery agents of NO 9-14. The release of free NO by iron nitrosyls has been examined in detail, yet very little work has been devoted to understanding the mechanism of NO-transfer from DNICs 15-18.…”