DNA damage, cell cycle perturbation and cell death by naphthalene diimide derivative in gastric cancer cells.

Stomach cancer causes the third-highest cancer-related deaths worldwide. Limited availability of anticancer measures with higher efficiency and low unwanted toxicities necessitates the development of better cancer chemotherapeutics. Naphthalene diimide (NDI) derivatives have gained significant attention owing to their excellent anticancer potential. We evaluated the anticancer properties of NDI derivatives, 1a and 2a in cancer cell lines and found that 1a showed higher efficacy as compared to 2a exhibiting a remarkable difference in activity upon single atom substitution of C with N. Particularly, NDI 1a showed potent inhibitory activity against gastric cancer cell line AGS with IC50 of 2.0 µM. NDI 1a induced remarkable morphological changes and reduced clonogenicity as well as the migratory ability of AGS cells. The reduction in AGS cell migration was mediated through inhibition of Tyr397 p-FAK dephosphorylation at focal adhesion points leading to enhanced attachment of cells at contact points. NDI 1a caused extensive DNA double-strand-breaks (DSBs) leading to activation of p53 and its transcriptional target p21. Reduced nuclear BRCA1 but enhanced nuclear p53BP1 foci formation upon 1a treatment suggests that DNA DSB repair is mediated through error-prone NHEJ which led to the accumulation of extensive DNA damage. Combinatorial effects mediated by interactions of 1a with double-stranded DNA through minor groove binding as well as induction of intracellular ROS exacerbated the loss of genomic integrity induced by 1a. NDI 1a mediated DNA damage-induced S phase arrest; however, cells experiencing extensive and irreparable DNA damage underwent mitochondrial apoptosis through downregulation of anti-apoptotic protein p21. Furthermore, proliferation inhibitory activity of 1a is also attributed to inhibition of ß-catenin/c-Myc axis in AGS cells with constitutively active ß-catenin pathway. In vivo toxicity analysis of 1a revealed minimal systemic toxicity suggesting that compound 1a is a safe and potential candidate for the development of gastric cancer chemotherapeutics.

Naphthalenediimides with High Fluorescence Quantum Yield: Bright-Red, Stable, and Responsive Fluorescent Dyes.

The naphthalenediimide (NDI) scaffold in contrast to its higher congeners possess low-fluorescence. In spite of elegant synthetic developments, a highly emissive NDI is quite rare to find, as well as, a green-light-emitting NDI is yet to be explored. Herein, we report a novel class of symmetric and asymmetric NH2 -substituted core-NDIs (1-5) with tunable fluorescence in the visible region and extending to the NIR frontier. Importantly, the bis-NH2 -substituted NDI 2 revealed quantum yield, Φ f of ≈81 and ≈68 % in toluene and DMSO, respectively, suggesting versatility of the fluorophore in a wide range of solvent polarity. The dye 1 is shown to be the first NDI-based green-light emitter. The donor piperidine group in 5 diminish the Φ f by 40-fold providing a lever to modulate the excited-state intramolecular proton transfer (ESIPT) process. Our synthetic protocol applies a Pd catalyst and a benign hydride source simplifying the non-trivial -NH2 group integration at the NDI-core. TD-DFT calculations predicted strong intramolecular hydrogen bonds in the excited state in the bulk nonpolar medium and responsiveness to solvent polarity. The maximization of the NDI emission outlined here would further boost the burgeoning repertoire of applications of the NDI scaffold.

Halogen-Bonded Assemblies of Arylene Imides and Diimides: Insight from Electronic, Structural, and Computational Studies.

Halogen-bonding interactions in electron-deficient π scaffolds have largely been underexplored. Herein, the halogen-bonding properties of arylene imide/diimide-based electron-deficient scaffolds were studied. The influence of scaffold size, from small (phthalimide) to moderately sized (pyromellitic diimide or naphthalenediimides) to large (perylenediimide), axial-group modification, and number of halo substituents on the halogen bonding and its self-assembly was probed in a set of nine compounds. The structural modification leads to tunable optical and redox properties. The first reduction potential E 1 / 2 1 ranges between -1.09 and -0.17 V (vs. SCE). Two of the compounds, that is, 6 and 9, have deep-lying LUMOs with values reaching -4.2 eV. Single crystals of all nine systems were obtained, which showed Br⋅⋅⋅O, Br⋅⋅⋅Br, or Br⋅⋅⋅π halogen-bonding interactions, and a few systems are capable of forming all three types. These interactions lead to halogen-bonded rings (up to 12-membered), which propagate to form stacked 1D, 2D, or corrugated sheets. A few outliers were also identified, for example, molecules that prefer C-H⋅⋅⋅O hydrogen bonding over halogen bonding, or noncentrosymmetric rather than centrosymmetric organization. Computational studies based on Atoms in Molecules and Natural Bond Orbital analysis provided further insight into the halogen-bonding interactions. This study can lead to a predictive design tool-box to further explore related systems on surfaces reinforced by these weak directional forces.

Doubly zwitterionic, di-reduced, highly electron-rich, air-stable naphthalenediimides: redox-switchable islands of aromatic-antiaromatic states.

The di-reduced state of the naphthalene moiety and its congeners have long captivated chemists as it is elusive to stabilize these intrinsically reactive electron-rich π-systems and for their emergent multifaceted properties. Herein we report the synthesis and isolation of two-electron (2e-) reduced, highly electron-rich naphthalenediimides (NDIs). A doubly zwitterionic structure is observed for the first time in a naphthalene moiety and validated by single crystal X-ray crystallography and spectroscopic methods. The synthesis avoids hazardous reducing agents and offers an easy, high-yielding route to bench-stable di-reduced NDIs. Notably, we realized high negative first oxidation potentials of up to -0.730 V vs. Fc/Fc+ in these systems, which establish these systems to be one of the strongest ambient stable electron donors. The study also provides the first insights into the NMR spectra of the di-reduced systems revealing a large decrease in diatropicity of the naphthalene ring compared to its 2e- oxidized form. The NICS, NICS-XY global ring current, gauge-including magnetically induced current (GIMIC) and AICD ring current density calculations revealed switching of the antiaromatic and aromatic states at the naphthalene and the imide rings, respectively, in the di-reduced system compared to the 2e- oxidized form. Notably, the substituents at the phosphonium groups significantly tune the antiaromatic-aromatic states and donor ability, and bestow an array of colors to the di-reduced systems by virtue of intramolecular through-space communication with the NDI scaffold. Computational studies showed intramolecular noncovalent interactions to provide additional stability to these unprecedented doubly zwitterionic systems.

Downregulation of c-Myc and p21 expression and induction of S phase arrest by naphthalene diimide derivative in gastric adenocarcinoma cells.

Naphthalene diimide (NDI) derivatives have been shown to exhibit promising antineoplastic properties. In the current study, we assessed the anticancer and anti-bacterial properties of di-substituted NDI derivative. The naphthalene-bis-hydrazimide, 1, negatively affected the cell viability of three cancer cell lines (AGS, HeLa and PC3) and induced S phase cell cycle arrest along with SubG0/G1 accumulation. Amongst three cell lines, gastric cancer cell line, AGS, showed the highest sensitivity towards the NDI derivative 1. Compound 1 induced extensive DNA double strand breaks causing p53 activation leading to transcription of p53 target gene p21 in AGS cells. Reduction in protein levels of p21 and BRCA1 suggested that 1 treated AGS cells underwent cell death due to accumulation of DNA damage as a result of impaired DNA damage repair. ß-catenin downregulation and consequently decrease in levels of c-Myc may have led to 1 induced AGS cell proliferation inhibition.1 induced AGS cell S phase arrest was mediated through CylinA/CDK2 downregulation. The possible mechanisms involved in anticancer activity of 1 includes ROS upregulation, induction of DNA damage, disruption of mitochondrial membrane potential causing ATP depletion, inhibition of cell proliferation and downregulation of antiapoptotic factors ultimately leading to mitochondria mediated apoptosis. Further compound 1 also inhibited H. pylori proliferation as well as H. pylori induced morphological changes in AGS cells. These findings suggest that NDI derivative 1 exhibits two-pronged anticancer activity, one by directly inhibiting cancer cell growth and inducing apoptosis and the other by inhibiting H. pylori.

Isolation of Tetracyano-Naphthalenediimide and Its Stable Planar Radical Anion.

Reported herein is the first isolation of tetracyano-naphthalenediimide [NDI(CN)4 ] and its radical anion, and structural elucidation through spectroscopic and X-ray diffraction studies. The radical anion shows remarkable stability and was purified by chromatography, which is unique for planar radical anions. The stability results from multiple hydrogen bonds to the counter ion and through an array of intramolecular noncovalent interactions. The radical anion revealed one of the strongest NDI π-π interactions (3.268 Å). Electrochemical studies of [NDI(CN)4 ] confirm its extraordinarily low-lying LUMO (-5.0 eV), rendering it one of the strongest electron-deficient planar π systems to be isolated. The manifold potential, which remained unknown to date, can now be explored for these open- and closed-shell planar π systems.

Ambient Water-Stable Dianionic Electron Donors: Intramolecular Noncovalent Conduits Assist Charge Delocalization.

Electron-rich π-conjugated dianions are known to be ambient unstable and their stabilization in ambient water is yet to be realized. We report the first example of an exceptionally stable naphthalenediimide-based dianion in ambient and hot water, forming one of the most stable redox-active dianion. The half-life (t1/2 ) of dianion (1 a2- ) is more than four months in ambient water. The dianionic state was confirmed by X-ray crystallography and by various spectroscopic methods. The noncovalent electronic conduits introduced for the first time in dianions, embrace nO →π*C≡N interactions and aid in delocalizing the dianionic charge as validated from theoretical studies. The dianions harness strong NIR absorption and electron donor ability to organic acceptors and metal ions, which make them suitable for potential green energy applications.

Assorted morphosynthesis: access to multi-faceted nano-architectures from a super-responsive dual π-functional amphiphilic construct.

An electronically segmented amphiphile was created by conjugating two π-functional units hydroxyquinoline and naphthalenediimide (HQ/NDI) for the first time. The differential electrostatic potential of the π-surfaces, H-bonding units, etc. trigger a manifold response and direct the assembly of a unique collection of seven diverse nano-architectures. Chiral assembly, distinct classes of fibers, 3-D sheets, and metallo-spheres/fibrils with µM levels of Co/Cu/Zn(ii) ions emerged from this new approach of assorted morphosynthesis under ambient conditions.

Single electron transfer-driven multi-dimensional signal read-out function of TCNQ as an "off-the-shelf" detector for cyanide.

Herein we report the first applications of TCNQ as a rapid and highly sensitive off-the-shelf cyanide detector. As a proof-of-concept, we have applied a kinetically selective single-electron transfer (SET) from cyanide to deep-lying LUMO orbitals of TCNQ to generate a persistently stable radical anion (TCNQ(•-)), under ambient condition. In contrast to the known cyanide sensors that operate with limited signal outputs, TCNQ(•-) offers a unique multiple signaling platform. The signal readability is facilitated through multichannel absorption in the UV-vis-NIR region and scattering-based spectroscopic methods like Raman spectroscopy and hyper Rayleigh scattering techniques. Particularly notable is the application of the intense 840 nm NIR absorption band to detect cyanide. This can be useful for avoiding background interference in the UV-vis region predominant in biological samples. We also demonstrate the fabrication of a practical electronic device with TCNQ as a detector. The device generates multiorder enhancement in current with cyanide because of the formation of the conductive TCNQ(•-).