Benzofuroxan

Solvent-Mediated Functionalization of Benzofuroxan on Electron-Rich Ruthenium Complex Platform.[Pubmed:29645363]

Chem Asian J. 2018 Jun 18;13(12):1582-1593.

An unprecedented reactivity profile of biochemically relevant R-Benzofuroxan (R=H, Me, Cl), with high structural diversity and molecular complexity on a selective {Ru(acac)2 } (acac=acetylacetonate) platform, in conjugation with EtOH solvent mediation, is revealed. This led to the development of monomeric [Ru(III) (acac)2 (L(1R) )] (1 a-1 c; L(1R) =2-nitrosoanilido derivatives) and dimeric [{Ru(II) (acac)2 }2 (L(2R) )] (2 a-2 b; L(2R) =(1E,2E)-N(1) ,N(2) -bis(2-nitrosophenyl)ethane-1,2-diimine derivatives) complexes in one pot with a change in the metal redox conditions. The functionalization of Benzofuroxan in 1 and 2 implied in situ reduction of N=O to NH(-) in the former and solvent-assisted multiple N-C coupling in the latter. The aforesaid transformation processes were authenticated through structural elucidation of representative complexes, and evaluated by their spectroscopic/electrochemical features, along with C2 D5 OD labeling and monitoring of the impact of substituents (R) in the Benzofuroxan framework on the product distribution process. The noninnocent potential of newly developed L(1) and L(2) in 1 and 2, respectively, was also probed by spectroelectrochemistry in combination with DFT calculations.

Ruthenium-Hydride Mediated Unsymmetrical Cleavage of Benzofuroxan to 2-Nitroanilido with Varying Coordination Mode.[Pubmed:28825793]

Inorg Chem. 2017 Sep 5;56(17):10735-10747.

The reaction of R-Benzofuroxan (R = H, Me, Cl) with the metal precursor [Ru(Cl)(H)(CO)(PPh3)3] (A) or [Ru(Cl)(H)(CH3CN)(CO)(PPh3)2] (B) in CH3CN at 298 K resulted in the intermediate complex [Ru(Cl)(L(1))(CH3CN)(CO)(PPh3)2] (L(1) = monodentate 2-nitroanilido) (1, pink), which however underwent slow transformation to the final product [Ru(Cl)(L(2))(CO)(PPh3)2] (L(2) = bidentate 2-nitroanilido) (2, green). On the contrary, the same reaction in refluxing CH3CN directly yielded 2 without any tractable intermediate 1. Structural characterization of the intermediates 1a-1c and the corresponding final products 2a-2c (R = H, Me, Cl) authenticated their identities, revealing ruthenium-hydride mediated unsymmetrical cleavage of Benzofuroxan to hydrogen bonded monodentate 2-nitroanilido (L(1)) in the former and bidentate 2-nitroanilido (L(2)) in the latter. The spectrophotometric monitoring of the transformations of B --> 1 as well as 1 --> 2 with time and temperature established the first order rate process with associatively activated pathway for both cases. Both 1 and 2 exhibited one reversible oxidation and an irreversible reduction within +/-1.5 V versus saturated calomel reference electrode in CH3CN with slight variation in potential based on substituents in the Benzofuroxan framework (R = H, Me, Cl). Spectroscopic (electron paramagnetic resonance and UV-vis) and density functional theory calculations collectively suggested varying contribution of metal based orbitals along with the ligand in the singly occupied molecular orbital of 1(+) or 2(+), ascertaining the noninnocent potential of the in situ generated (L(1)) or (L(2)).

Novel Structural Hybrids on the Base of Benzofuroxans and Furoxans. Mini-Review.[Pubmed:27697059]

Curr Top Med Chem. 2017;17(9):986-1005.

Hybrid drug strategy is based on the combination of two or more pharmacophores into a new chemical entity to improve the properties of the original compounds or to obtain double action of resulting molecule. Hybrid molecules, comprised of some pharmacophore and nitric oxide (NO) donor moiety, constitute one of the more promising approaches for the design of drugs. Furoxans and Benzofuroxans are considered NO releasing prodrugs and are of great interest for researchers. In this review we will focus on furoxan and Benzofuroxan hybrids described in literature during the last years (from 2005 to 2016).

BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity.[Pubmed:26876618]

Toxicol Appl Pharmacol. 2016 Mar 15;295:56-67.

Benzofuroxan is an interesting ring system, which has shown a wide spectrum of biological responses against tumor cell lines. We investigated, herein, the antitumor effects of Benzofuroxan derivatives (BFDs) in vitro and in a melanoma mouse model. Cytotoxic effects of twenty-two BFDs were determined by MTT assay. Effects of BFD-22 in apoptosis and cell proliferation were evaluated using Annexin V-FITC/PI and CFSE staining. In addition, the effects in the cell cycle were assessed. Flow cytometry, western blot, and fluorescence microscopy analysis were employed to investigate the apoptosis-related proteins and the BRAF signaling. Cell motility was also exploited through cell invasion and migration assays. Molecular docking approach was performed in order to verify the BFD-22 binding mode into the ATP catalytic site of BRAF kinase. Moreover, the BFD-22 antitumor effects were evaluated in a melanoma murine model using B16F10. BFD-22 was identified as a potential hit against melanoma cells. BFD-22 induced apoptosis and inhibited cell proliferation of B16F10 cells. BFD-22 has suppressed, indeed, the migratory and invasive behavior of B16F10 cells. Cyclin D1 and CDK4 expression were reduced leading to cell cycle arrest at G0/G1 phase. Of note, phosphorylation of BRAF at Ser338 was strongly down-regulated by BFD-22 in B16F10 cells. The accommodation/orientation into the binding site of BRAF was similar of BAY43-9006 (co-crystallized inhibitor of BRAF, sorafenib). Importantly, BFD-22 presented in vivo antimetastatic effects and showed better therapeutic efficacy than sorafenib and taxol. BFD-22 can be considered as a new lead compound and, then, can be helpful for the designing of novel drug candidates to treat melanoma.

Synthesis of New 'Hybrid' Compounds Based on Benzofuroxans and Aminoalkylnaphthalimides.[Pubmed:26575416]

Chem Biol Drug Des. 2016 Apr;87(4):626-34.

Pathogenic bacteria and fungi eventually develop resistance to existing drugs, and therefore, we need constant development of new drugs. The research is aimed at addressing fundamental scientific problems-the search for new biologically active compounds among several Benzofuroxan-containing 'hybrid' products. N-substituted naphthalimides were chosen as a second pharmacophore. Benzofuroxanes biological effects were studied by means of bacterial lux-biosensors. Compounds IIIa, IVa, IIIc, and IVc displayed more expressed bacteriotoxic action in comparison with the initial substances Ia-c and represent a certain interest for using as antibacterial substances.

Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo.[Pubmed:26503030]

BMC Cancer. 2015 Oct 27;15:807.

BACKGROUND: Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by Benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different Benzofuroxan derivatives in a murine melanoma model. METHODS: B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins. RESULTS: Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase -9, -3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM. CONCLUSION: We conclude that N-Br and N-I are promising agents aiming at cancer treatment. They may be useful in melanoma therapy as inducers of intrinsic apoptosis and by exerting significant antitumor activity against metastatic melanoma, as presently shown in syngeneic mice.