Synthesis and characterization of organoselenium based BODIPY and its application in living cells.

Phenylselenide based BODIPY probe was successfully synthesized and characterized by NMR spectroscopic techniques (1H, 13C and 77Se NMR), mass spectrometry and single crystal XRD. Surprisingly, crystal packing diagram of the probe showed formation of 1-D strip through intermolecular F---H interaction. The probe was screened with various Reactive Oxygen Species (ROS) and found to be selective for superoxide ion over other ROS via "turn-on" fluorescence response. The probe selectively and sensitively detects superoxide with a lower detection limit (43.34 nM) without interfering with other ROS. The quantum yield of the probe was found to increase from 0.091 % to 30.4 % (334-fold) after oxidation. Theoretical calculations (DFT and TD-DFT) were also performed to understand the sensing mechanism of the probe. The probe was able to effectively detect superoxide inside living cells without any toxic effect.

Synthesis and evaluation of N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides and their N-ethyl analogous as anticancer, anti-angiogenic & antioxidant agents: In vitro and in silico analysis.

N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides and their N-ethyl analogues (flutamides) are versatile scaffolds with a wide spectrum of biological activities. A series of new N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides (8a-t) and their N-ethyl analogous (9a-t) were synthesized and characterized. The inhibitory potential of the synthesized compounds on the viability of three human cancer cell lines HEP3BPN 11 (liver), MDA-MB 453 (breast), and HL 60 (leukemia) were assessed. Among all the compounds 8 L, 8q, 9n and 9p showed higher inhibitory activity on the viability of HL 60 than the standard methotrexate. These lead molecules were then tested for their potential to inhibit the activity of proangiogenic cytokines. The compound 9n showed significantly better inhibition against two cytokines viz. TNFα and Leptin as compared to the standard suramin, while 9p has activity comparable to suramin against IGF1, VEGF, FGFb, and Leptin. The 8q is found to be strong antiangiogenic agent against IGF1, VEGF and TGFß; while 8 L has showed activity against TNFα, VEGF, and Leptin inhibition. Furthermore antioxidant potential of 8a-t and 9a-t compounds was screened using DPPH, OH and SOR radical scavenging activities. The OH radical scavenging activity of 8c and DPPH activities of 9n as well as 9o are significant as compared to respective standards ascorbic acid and α-tocopherol. The 8c, 9p and 9 h have also exhibited potential antioxidant activity. Additionally, we present in silico molecular docking data to provide the structural rationale of observed TNFα inhibition against newly synthesized compounds. Overall, the synthesized flutamide derivatives have not only anticancer activity, but also possess dual inhibitory effect (anti-angiogenesis and antioxidant) and hence can act as a promising avenue to develop further anticancer agents.

Exploiting the unique specialty of hydrazone functionality: Synthesis of a highly sensitive UV-Vis active solvatochromic probe.

The unique physico-chemical attributes of the hydrazone functionality have been extensively studied for a diverse range of chemical, biological and analytical applications. The synthesis of a highly sensitive hydrazone based UV-Vis active solvatochromic probe that exhibits excellent sensitivity toward sensing of solvent polarity, microstructural changes and onset of micellization in aqueous systems was carried out. Specifically, synthesis of 2,4-dinitrophenyl-2-(2-nitrobenzylidene)hydrazone (DNPNBH), through an easy to carry, atom economical, one-pot single step approach via use of low-cost precursors viz. ortho-nitrobenzaldehyde and 2,4-dinitrophenyl hydrazine is presented. The UV-Vis absorption features of the synthesized hydrazone exhibit excellent sensitivity toward the polarity of its immediate microenvironment. The microenvironment polarity sensing potential of DNPNBH is demonstrated for some single solvent systems and DMF-Water mixture as a model binary solvent system and the results are supported by quantum mechanical calculations. Use of the DNPNBH as a probe (at concentrations many orders lower than required for conventional probes) to precisely reflect the onset of micellization and estimation of critical micelle concentration (CMC) of amphiphilic molecules (5.25 mM for SDS, 1.53 mM for CTAB and 0.055 mM for Brij56) in aqueous solutions is also demonstrated. The results clearly qualify the synthesized hydrazone as a highly sensitive UV-Vis probe that can be employed for reliable sensing of solvent polarity, composition dependence of physicochemical attributes in mixed solvent systems and the estimation of CMC of surfactant systems via spectrophotometry.

Fingerprinting Electronic Structure of Heme Iron by Ab Initio Modeling of Metal L-Edge X-ray Absorption Spectra.

The capability of the multiconfigurational restricted active space approach to identify electronic structure from spectral fingerprints is explored by applying it to iron L-edge X-ray absorption spectroscopy (XAS) of three heme systems that represent the limiting descriptions of iron in the Fe-O2 bond, ferrous and ferric [Fe(P)(ImH)2]0/1+ (P = porphine, ImH = imidazole), and FeII(P). The level of agreement between experimental and simulated spectral shapes is calculated using the cosine similarity, which gives a quantitative and unbiased assignment. Further dimensions in fingerprinting are obtained from the L-edge branching ratio, the integrated absorption intensity, and the edge position. The results show how accurate ab initio simulations of metal L-edge XAS can complement calculations of relative energies to identify unknown species in chemical reactions.

Luminescent Ruthenium(II) Polypyridyl Complexes as Nonviral Carriers for DNA Delivery.

Two new luminescent ruthenium(II) polypyridyl complexes, [Ru(bpy)2 (tpt-phen)]Cl2 (1; bpy=2,2'-bipyridine, tpt-phen=triptycenyl-1,10-phenanthroline) and [Ru(phen)2 (tpt-phen)]Cl2 (2; phen=1,10-phenanthroline), have been developed as potential nonviral vectors for DNA delivery. Photophysical and electrochemical properties of the complexes have been investigated and corroborated with electronic structure calculations. DNA condensation by these complexes has been investigated by UV/Vis and emission spectroscopy, circular dichroism spectroscopy, atomic force microscopy, dynamic light scattering, confocal microscopy, and electrophoretic mobility studies. These complexes interact with DNA and efficiently condense DNA into globular nanoparticles that are taken up efficiently by HeLa cells. DNA cleavage inability and biocompatibility of complexes have been explored. Both complexes have good gene transfection abilities.

Molecular Orbital Simulations of Metal 1s2p Resonant Inelastic X-ray Scattering.

For first-row transition metals, high-resolution 3d electronic structure information can be obtained using resonant inelastic X-ray scattering (RIXS). In the hard X-ray region, a K pre-edge (1s→3d) excitation can be followed by monitoring the dipole-allowed Kα (2p→1s) or Kß (3p→1s) emission, processes labeled 1s2p or 1s3p RIXS. Here the restricted active space (RAS) approach, which is a molecular orbital method, is used for the first time to study hard X-ray RIXS processes. This is achieved by including the two sets of core orbitals in different partitions of the active space. Transition intensities are calculated using both first- and second-order expansions of the wave vector, including, but not limited to, electric dipoles and quadrupoles. The accuracy of the approach is tested for 1s2p RIXS of iron hexacyanides [Fe(CN)6](n-) in ferrous and ferric oxidation states. RAS simulations accurately describe the multiplet structures and the role of 2p and 3d spin-orbit coupling on energies and selection rules. Compared to experiment, relative energies of the two [Fe(CN)6](3-) resonances deviate by 0.2 eV in both incident energy and energy transfer directions, and multiplet splittings in [Fe(CN)6](4-) are reproduced within 0.1 eV. These values are similar to what can be expected for valence excitations. The development opens the modeling of hard X-ray scattering processes for both solution catalysts and enzymatic systems.

Viewing the Valence Electronic Structure of Ferric and Ferrous Hexacyanide in Solution from the Fe and Cyanide Perspectives.

The valence-excited states of ferric and ferrous hexacyanide ions in aqueous solution were mapped by resonant inelastic X-ray scattering (RIXS) at the Fe L2,3 and N K edges. Probing of both the central Fe and the ligand N atoms enabled identification of the metal- and ligand-centered excited states, as well as ligand-to-metal and metal-to-ligand charge-transfer excited states. Ab initio calculations utilizing the RASPT2 method were used to simulate the Fe L2,3-edge RIXS spectra and enabled quantification of the covalencies of both occupied and empty orbitals of π and σ symmetry. We found that π back-donation in the ferric complex is smaller than that in the ferrous complex. This is evidenced by the relative amounts of Fe 3d character in the nominally 2π CN(-) molecular orbital of 7% and 9% in ferric and ferrous hexacyanide, respectively. Utilizing the direct sensitivity of Fe L3-edge RIXS to the Fe 3d character in the occupied molecular orbitals, we also found that the donation interactions are dominated by σ bonding. The latter was found to be stronger in the ferric complex, with an Fe 3d contribution to the nominally 5σ CN(-) molecular orbitals of 29% compared to 20% in the ferrous complex. These results are consistent with the notion that a higher charge at the central metal atom increases donation and decreases back-donation.

Simulations of iron K pre-edge X-ray absorption spectra using the restricted active space method.

The intensities and relative energies of metal K pre-edge features are sensitive to both geometric and electronic structures. With the possibility to collect high-resolution spectral data it is important to find theoretical methods that include all important spectral effects: ligand-field splitting, multiplet structures, 3d-4p orbital hybridization, and charge-transfer excitations. Here the restricted active space (RAS) method is used for the first time to calculate metal K pre-edge spectra of open-shell systems, and its performance is tested against on six iron complexes: [FeCl6](n-), [FeCl4](n-), and [Fe(CN)6](n-) in ferrous and ferric oxidation states. The method gives good descriptions of the spectral shapes for all six systems. The mean absolute deviation for the relative energies of different peaks is only 0.1 eV. For the two systems that lack centrosymmetry [FeCl4](2-/1-), the ratios between dipole and quadrupole intensity contributions are reproduced with an error of 10%, which leads to good descriptions of the integrated pre-edge intensities. To gain further chemical insight, the origins of the pre-edge features have been analyzed with a chemically intuitive molecular orbital picture that serves as a bridge between the spectra and the electronic structures. The pre-edges contain information about both ligand-field strengths and orbital covalencies, which can be understood by analyzing the RAS wavefunction. The RAS method can thus be used to predict and rationalize the effects of changes in both the oxidation state and ligand environment in a number of hard X-ray studies of small and medium-sized molecular systems.

Cost and sensitivity of restricted active-space calculations of metal L-edge X-ray absorption spectra.

The restricted active-space (RAS) approach can accurately simulate metal L-edge X-ray absorption spectra of first-row transition metal complexes without the use of any fitting parameters. These characteristics provide a unique capability to identify unknown chemical species and to analyze their electronic structure. To find the best balance between cost and accuracy, the sensitivity of the simulated spectra with respect to the method variables has been tested for two models, [FeCl6 ](3-) and [Fe(CN)6 ](3-) . For these systems, the reference calculations give deviations, when compared with experiment, of ≤1 eV in peak positions, ≤30% for the relative intensity of major peaks, and ≤50% for minor peaks. When compared with these deviations, the simulated spectra are sensitive to the number of final states, the inclusion of dynamical correlation, and the ionization potential electron affinity shift, in addition to the selection of the active space. The spectra are less sensitive to the quality of the basis set and even a double-ζ basis gives reasonable results. The inclusion of dynamical correlation through second-order perturbation theory can be done efficiently using the state-specific formalism without correlating the core orbitals. Although these observations are not directly transferable to other systems, they can, together with a cost analysis, aid in the design of RAS models and help to extend the use of this powerful approach to a wider range of transition metal systems.

Restricted active space calculations of L-edge X-ray absorption spectra: from molecular orbitals to multiplet states.

The metal L-edge (2p → 3d) X-ray absorption spectra are affected by a number of different interactions: electron-electron repulsion, spin-orbit coupling, and charge transfer between metal and ligands, which makes the simulation of spectra challenging. The core restricted active space (RAS) method is an accurate and flexible approach that can be used to calculate X-ray spectra of a wide range of medium-sized systems without any symmetry constraints. Here, the applicability of the method is tested in detail by simulating three ferric (3d(5)) model systems with well-known electronic structure, viz., atomic Fe(3+), high-spin [FeCl6](3-) with ligand donor bonding, and low-spin [Fe(CN)6](3-) that also has metal backbonding. For these systems, the performance of the core RAS method, which does not require any system-dependent parameters, is comparable to that of the commonly used semi-empirical charge-transfer multiplet model. It handles orbitally degenerate ground states, accurately describes metal-ligand interactions, and includes both single and multiple excitations. The results are sensitive to the choice of orbitals in the active space and this sensitivity can be used to assign spectral features. A method has also been developed to analyze the calculated X-ray spectra using a chemically intuitive molecular orbital picture.

Encapsulation of alkyl and aryl derivatives of quaternary ammonium cations within cucurbit[n]uril (n = 6,7) and their inverted diastereomers: density functional investigations.

Electronic structure, vibrational frequencies, and ¹H chemical shifts of inclusion complexes between CB[n] (n = 6,7) or their inverted iCB[n] diastereomer hosts and quaternary diammonium viz., 1,6-hexyldiammonium (HDA) or p-xylyldiammonium (XYL) cationic guests are obtained from the density functional calculations. The interaction of CB[n] or iCB[n] with HDA (guest) conduce inclusion complexes in which the guest attains gauche conformation within the host cavity. The lowest energy XYL complexes of CB[6] or iCB[6] are comprised of one ammonium group orienting parallel to aromatic ring. The CB[7] or iCB[7] complexes of XYL on the other hand, reveal ammonium group(s) perpendicular to aromatic ring of the guest. The ureido C=O and N--H stretching vibrations on complexation engender frequency down-shift in the calculated spectra. This can be attributed to C--H-- --O and N--H-- --O interactions in the complex. The inverting of glycouril unit in iCB[n] renders a frequency shift (12 cm⁻¹) for the C=O stretching in the opposite direction. Molecular electron density topography and natural bond orbital analyses have been used to explain the direction of frequency shifts. Calculated ¹H NMR reveal that guest protons within the host cavity not participating in hydrogen bonding interactions, exhibit shielded signals compared to isolated XYL or HDA. Likewise the inverted protons in the iCB[6]-XYL complex led to up-field signals in calculated ¹H NMR as a result of C-H-- -π interactions.

Binding of rhodamine B and kiton red S to cucurbit[7]uril: density functional investigations.

The binding of the laser dyes rhodamine B (RhB) and sulforhodamine B (kiton red S or KRS) to a cucurbit[7]uril (CB[7]) host has been investigated using density functional theory. Both guests (RhB and KRS) contain two N,N-diethylamino groups on a xanthene core. The lowest-energy structure of these host-guest complexes has one of the N,N-diethylamino groups encapsulated within the host cavity, that engenders C-H···O interactions with portals, while the remaining noninteracting diethylamino group resides outside the cavity. The (1)H NMR chemical shifts derived using the gauge-independent atomic orbital method are consistent with those observed in experiments.

Electronic structure, molecular electrostatic potentials, vibrational spectra in substituted calix[n]arenes (n = 4, 5) from density functional theory.

Electronic structure, molecular electrostatic potential, and vibrational frequencies of para-substituted calix[n]arene CX[n]-R (n = 4, 5; R = H, NH(2), t-Bu, CH(2)Cl, SO(3)H, NO(2)) and their thia analogs (S-CX[n]-R; with R = H and t-Bu) in which sulfur bridges two aromatic rings of CX[n] have been derived from the density functional theory. A rotation around CH(2) groups connecting the phenol rings engenders four, namely, cone, partial cone, 1,2-alternate, and 1,3-alternate CX[n]-R conformers. Of these, the cone conformer comprising of large number of O1-H1···O1' interactions turns out to be of lowest energy. Normal vibration analysis reveal the O1-H1 stretching frequency of unsubstituted CX[n] shifts to higher wavenumber (blue shift) on substitution of electron-withdrawing (NO(2) or SO(3)H) groups, while electron-donating substituents (NH(2), t-Bu) engender a shift of O1-H1 vibration in the opposite direction (red shift). The direction of frequency shifts have been analyzed using natural bond orbital analysis and molecular electrostatic potential (MESP) topography. Furthermore, calculated (1)H NMR chemical shift (δ(H)) in modified CX[n] hosts follow the order: H1 > H3/H5 > H7(a) > H7(b). The δ(H) values in CX[4] are in consonant with the observed (1)H NMR spectra.

Electronic structure and (1)H NMR chemical shifts in host-guest complexes of cucurbit[6]uril and sym-tetramethyl cucurbit[6]uril with imidazole derivatives.

Binding patterns and (1)H NMR chemical shifts in the complexes of protonated N-(4-hydroxylphenyl)imidazole (g1), N-(4-aminophenyl)imidazole (g2), 2-phenylimidazole (g3) guests with cucurbit[6]uril (CB[6]), and sym-substituted tetramethyl cucurbit[6]uril (TMeCB[6]) in the gas phase as well as in water have been investigated using the density functional theory. It has been shown that the inclusion complexes of g1 and g2 with CB[6] or TMeCB[6] exhibit selective encapsulation of the phenyl moiety with its substituents binding to portal oxygens on the lower rim of the host and imidazole protons facilitate C-H···O interactions externally with upper rim ureido oxygens. On the other hand, the lowest-energy g3 complex encapsulates the imidazole ring within the host, engendering N-H···O interactions with portal oxygens on the upper rim of the host with the phenyl ring residing outside the cavity owing to an absence of para-substituent and show qualitatively different host-guest binding patterns. Calculated (1)H NMR spectra of the complexes in water reveal shielding of phenyl ring protons within the host cavity which exhibit signals at 0.2-0.5 ppm, whereas the protons of the imidazole ring participating in hydrogen bonded interactions exhibit deshielding, and the corresponding (1)H NMR signals are downshifted by 1.1-1.5 ppm in the spectra compared to those in the unbound guest. (1)H NMR chemical shifts of inclusion complexes thus obtained are in consonant with δ(H) patterns observed in experiments reported in the literature.

Electronic structure and normal vibrations in (+)-catechin and (-)-epicatechin encapsulated beta-cyclodextrin.

Host-guest interactions between beta-cyclodextrin (beta-CD) and flavan-3-Ol enantiomers (guest) namely, (+)-catechin (CA) or (-)-epicatechin (EC), have been analyzed within the framework of density functional theory. Both CA and EC consist of two phenol rings, I and II, and a pyran ring, III, which facilitate a variety of binding patterns with the host, beta-CD. The minimum energy beta-CD-CA complex reveals that ring II of CA interacts with primary hydroxyls of the upper rim and the phenol ring I engenders hydrogen-bonded interactions with secondary hydroxyl from the lower rim of CD. On the other hand, the O-H...O interactions between ring I and primary hydroxyls of beta-CD along with those between one of hydroxyl of ring II and secondary hydroxyl of the host render large stability to the beta-CD-EC complex. Structures of both beta-CD-CA and beta-CD-EC complexes thus obtained are in consonant with those inferred from the experimental NMR data and exhibit distinct features in infrared spectra. The frequency shifts of characteristic vibrations in infrared spectra of these complexes compared to the unbound individual host or guest in its free state have been analyzed with the use of natural bond orbital analyses and combining difference electron density maps with bond critical points in molecular electron density topography.

Synthesis, computational study and glycosidase inhibitory activity of polyhydroxylated conidine alkaloids--a bicyclic iminosugar.

New bicyclic conidine iminosugars 1d and 1e were synthesized from D-glucose. Thus, D-glucose was converted to sugar beta-amino acids 3a and 3b in good yields. Individual treatment of 3a/3b with the Mukaiyama reagent afforded sugar beta-lactams 4a/4b that on reduction with LiAlH(4)/AlCl(3) gave azetidines 5a/5b with a sugar appendage. Reductive aminocyclization of sugar azetidines 5a/5b afforded the corresponding conidine iminosugars 1d/1e. Based on the (1)H NMR and DFT calculation studies the conformation of 1d was assigned as half chair A2 and that of 1e as a boat B2. The glycosidase inhibitory activities of 1d and 1e such as alpha-mannosidase, alpha-glucosidase and alpha-galactosidase were studied. The alpha-amylase activity was compared with acarbose. Compound 1d was found to be a moderate inhibitor of glycosidases while 1e was noticed to be a good inhibitor of alpha-mannosidase and a moderate inhibitor of other glycosidases. These results were substantiated by molecular docking studies using WHAT IF software and the AUTODOCK 3.0 program.

Density functional investigations on the charge distribution, vibrational spectra, and NMR chemical shifts in cucurbit[n]uril (n = 5-12) hosts.

Electronic structure, charge distribution, and vibrational frequencies of cucurbit[n]uril, CB[n] (n = 5-12), hosts have been derived using the density functional methods. CB[n] conformers with different orientations of methylene group connecting glycouril units have been investigated. The conformers that possess uniform CB[n] cavity turn out to be of lowest energy, and molecular electrostatic potential (MESP) herein engender shallow minima near ureido oxygens along the series. MESP topography has been utilized to estimate the cavity height and diameter; the ratio of which governs the shape (circular or elliptical) of the cavity. When this ratio is larger than unity (for CB[n] with n >or= 8), an elliptical host cavity is noticed. Calculated vibrational spectra reveal that carbonyl stretching frequency shift in successive CB[n] homologue decreases steadily from 1760 cm(-1) in CB[5] to 1742 cm(-1) in CB[12]. An increase in glycouril units along the CB[n] series influences significantly the intensity profile of C horizontal lineO and C-N stretching vibrations in the calculated infrared spectra. Furthermore, calculated (1)H chemical shifts predict that one of methylene protons directing outside the host cavity are deshielded, whereas the remaining proton near the carbonyl group exhibits downshifted signal in the NMR spectra.

On the binding of SF6 to cucurbit[6]uril host: density functional investigations.

Interactions of sulfur hexafluoride (SF(6)) with cucurbit[6]uril (CB[6]) have been investigated using the density functional calculations. An encapsulation of guest within CB[6] cavity as well as its binding to either exterior host protons or portal uredio oxygens have been analyzed. The present calculations predict that the complexes with the complete inclusion of SF(6) are favored over those possessing lateral or external interactions. The interactions between fluorine and ureido carbons (F---C) of the host contribute to lowering of energy of the complex. Normal mode analyses from the calculated vibrational spectra show a red-shifted stretching (approximately 928 cm(-1)) of S-F bonds perpendicular to the CB[6] cavity axis when SF(6) is encapsulated in the host cavity. On the other hand, S-F bonds parallel to the cavity axis exhibit a blue shift as compared to the corresponding vibration of the isolated guest. These frequency shifts of S-F bonds have further been analyzed by mapping the difference electron density on the bond critical point(s) (bcp) in molecular electron density (MED) topography and natural bond orbital (NBO) analyses. A depletion of electron density at the bcp along with an enhanced electron density in antibonding S-F* orbital engender weakening of the bond. Concomitant redistribution of electron density leads to the strengthening of S-F bonds parallel to the cavity axis (directing toward either portals). (1)H NMR reveals that the protons directing toward CB[n] portals are not influenced by encapsulation of the guest, which is in consonant with experimentally measured NMR spectra.

Synthesis and conformational study of chiral oxepines: the Baylis-Hillman reaction and RCM approach with sugar aldehyde.

The Baylis-Hillman reaction of 3-O-allyl-alpha-d-xylo-pentodialdo-1,4-furanose 3 afforded a diastereomeric mixture of d-gluco- and l-ido-configured alpha-methylene-beta-hydroxy esters 4a and 4b, respectively, in a ratio of 2:3. Reduction of the ester functionality in 4a/4b gave alcohols 5a/5b. The diene thus formed in 5a/5b was subjected to ring-closing metathesis (Grubbs' second-generation catalyst) to afford oxa-bicyclic ring system 6a/6b in high yield. Further manipulation of the acetonide functionality in 6a and 6b afforded new polyhydroxylated oxepines 1a/2a and 1b/2b, respectively. The (1)H NMR of oxepines 1a and 1b in D(2)O showed doubling of signals indicating their existence in two different rotamers/conformers. This fact was substantiated by calculating energetics of 1 and 2 conformers using the density functional theory and correlating the calculated (1)H NMR chemical shift pattern with that of the experimental spectra.