Phenyl carbohydrazone conjugated 2-oxoindoline as a new scaffold that augments the DNA and BSA binding affinity and anti-proliferative activity of a 1,10-phenanthroline based copper(II) complex

A new type of copper(II) complex, CuL(phen)(2)](NO3) (CuIP), where L ((E)-N'-(2-oxoindolin-3-ylidene) benzohydrazide) is a N donor ligand and phen is the N, N-donor heterocyclic 1,10-phenanthroline, has been synthesized. The phenyl carbohydrazone conjugated isatin-based ligand L and CuIP were characterized by elemental analysis, infrared, UV-Vis, H-1 and C-13 NMR and ESI-mass spectral data, as well as single-crystal X-ray diffraction. The interaction of calf thymus DNA (CT DNA) with L and CuIP has been investigated by absorption, fluorescence and viscosity titration methods. The complex CuIP displays better binding affinity than the ligand L. The observed DNA binding constant (K-b = 4.15(+/- 0.18) x 10(5) M-1) and binding site size (s = 0.19), viscosity data together with molecular docking studies of CuIP suggest groove binding and/or a partial intercalative mode of binding to CT DNA. In addition, CuIP shows good binding propensity to the bovine serum albumin (BSA) protein, giving a K-BSA value of 1.25(+/- 0.24) x 10(6) M-1. In addition, the docking studies on DNA and human serum albumin (HSA) CuIP interactions are consistent with the consequence of binding experiments. The in vitro anti-proliferative study establishes the anticancer potency of the CuIP against the human cervical (HeLa) and breast (MCF7) cancer cells; noncancer breast epithelial (MCF10a) cells have also been investigated. CuIP shows better cytotoxicity and sensitivity towards cancer cells over noncancer ones than L under identical conditions, with the appearance of apoptotic bodies. (C) 2014 Elsevier B.V. All rights reserved.

Regioselective Synthesis of Nitrofuran Containing Novel Spiropyrrolidine Library through 1,3-Dipolar Cycloaddition Reactions

A novel series of nitrofuran containing spiropyrrolidines has been synthesized with high regioselectivity in moderate to excellent yields via 1,3-dipolar cycloaddition reaction of azomethine ylides with various substituted chalcones.

First hyperpolarizability of Ru-half-sandwich complexes: The effect of halogen atom substitution on the ancillary ligand

The first hyperpolarizability (beta) of a series of half-sandwich Ru complexes with a mercaptobenzothiazole ligand bearing a halogen atom substitution in the para-position has been investigated by hyper-Rayleigh scattering and quantum chemical calculations. The heterocyclic ligand with a bromine atom in the para position makes it a very good donor and charge flows to the Ru center enhancing the beta value of the complex by a factor of 2 compared to the complex with the ligand without the halogen substitution. The resonance (+R) and the inductive (-I) effects exerted by the halogen atom in the para position push electrons in opposing directions in the complex. For the Br and Cl atoms the resonance effect dominates which enables the ligand to donate electrons to the metal center thereby increasing the hyperpolarizability whereas for the fluorine atom, the inductive effect is dominant which reduces the charge flow to the metal and the hyperpolarizability drops even below that of the unsubstituted ligand. This unprecedented halogen atom effect on beta of metal complexes is reported. (C) 2015 Elsevier By. All rights reserved.

An Easy Access to Benzofurans via DBU Induced Condensation Reaction of Active 2-Hydroxy Acetophenones with Phenacyl Chlorides: A Novel Class of Antioxidant Agents

A convenient and efficient one-pot synthesis of benzofurans 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t has been described from 2-hydroxy acetophenones and phenacyl chlorides in the presence of DBU. The procedure was applicable for a variety of phenacyl chlorides and provides a variety of benzofurans with higher yields. DBU acts as a base and as well as nucleophiles. All the derivatives were subjected to in vitro antioxidant screenings against representative 2,2-diphenyl-1-picryl-hydrazyl and 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radicals and results worth for further investigations.

Iodine promoted alpha-hydroxylation of ketones

A novel method for alpha-hydroxylation of ketones using substoichiometric amount of iodine under metalfree conditions is described. This method has been successfully employed in synthesizing a variety of heterocyclic compounds, which are useful precursors. alpha-Hydroxylation of diketones and triketones are illustrated. This strategy provides a novel, efficient, mild and inexpensive method for alpha-hydroxylation of aryl ketones using a sub-stoichiometric amount of molecular iodine.

Contrasting Electronic Requirements for C-H Binding and C-H Activation in d(6) Half-Sandwich Complexes of Rhenium and Tungsten

A computational study of the interaction half-sandwich metal fragments (metal=Re/W, electron count=d(6)), containing linear nitrosyl (NO+), carbon monoxide (CO), trifluorophosphine (PF3), N-heterocyclic carbene (NHC) ligands with alkanes are conducted using density functional theory employing the hybrid meta-GGA functional (M06). Electron deficiency on the metal increases with the ligand in the order NHC < CO < PF3 < NO+. Electron-withdrawing ligands like NO+ lead to more stable alkane complexes than NHC, a strong electron donor. Energy decomposition analysis shows that stabilization is due to orbital interaction involving charge transfer from the alkane to the metal. Reactivity and dynamics of the alkane fragment are facilitated by electron donors on the metal. These results match most of the experimental results known for CO and PF3 complexes. The study suggests activation of alkane in metal complexes to be facile with strong donor ligands like NHC. (C) 2015 Wiley Periodicals, Inc.

Synthesis of Novel Benzofuran-Gathered C-2,4,6-substituted Pyrimidine Derivatives Conjugated by Sulfonyl Chlorides: Orally Bioavailable, Selective, Effective Antioxidants and Antimicrobials Drug Candidates

In the present study, we have made an effort to develop the novel synthetic antioxidants and antimicrobials with improved potency. The novel benzofuran-gathered C-2,4,6-substituted pyrimidine derivatives 5a, 5b, 5c, 5d, 5e, 5f, 6a, 6b, 6c, 6d, 6e, 6f, 7a, 7b, 7c, 7d, 7e, 7f, 8a, 8b, 8c, 8d, 8e, 8f, 9a, 9b, 9c, 9d, 9e, 9f were synthesized by simple and efficient four-step reaction pathway. Initially, o-alkyl derivative of salicylaldehyde readily furnish corresponding 2-acetyl benzofuran 2 in good yield, upon the treatment with potassium tertiary butoxide in the presence of molecular sieves. Further, Claisen-Schmidt condensation with aromatic aldehydes via treatment with thiourea followed by coupling reaction with different sulfonyl chlorides afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, mass, and elemental analysis and further screened for their antioxidant and antimicrobial activities. The results showed that the synthesized compounds 8b, 8e, 9b, and 9e produced significant antioxidant activity with 50% inhibitory concentration higher than that of reference, whereas compounds 7d and 7c produced dominant antimicrobial activity at concentrations 1.0 and 0.5mg/mL compared with standard Gentamicin and Nystatin, respectively.

Synthesis of Optically Active 2-Amino-1,3,4-oxadiazoles and their Hybrid Peptides

Synthesis of 2-amino-1,3,4-oxadiazole derivatives of N-Cbz(benzyloxycarbonyl)/Boc-protected amino/peptide acids under sonication is described. The conditions involved in the present protocol are simple, mild, and racemization free. The utility of 2-amino group in the substituted oxadiazoles for the incorporation of peptide and ureido bonds to obtain hybrid peptidomimetics is also delineated. The 2-amino-1,3,4-oxadiazole 3b was obtained as a single crystal, and its molecular structure has been confirmed through X-ray crystallographic study.

Substituent Effects on the Stability and Antioxidant Activity of Spirodiazaselenuranes

Spirodiazaselenuranes are structurally interesting compounds and the stability of these compounds depends highly on the nature of the substituents attached to the nitrogen atoms. Aromatic substituents are known to play important roles in stabilizing the Se-N bonds in spiro compounds. In this study, several spirodiazaselenuranes are synthesized by introducing benzylic and aliphatic substituents to understand their effect on the stability of the Se-N bonds and the antioxidant activity. Replacement of phenyl substituent by benzyl/alkyl groups significantly reduces the stability of the spirodiazaselenuranes and slows down the oxidative cyclization process. The selenium centre in the spiro compounds undergoes further oxidation to produce the corresponding selenurane oxides, which are stable at room temperature. Comparison of the glutathione peroxidase (GPx) mimetic activity of the compounds showed that the diaryl selenides having heterocyclic rings are significantly more active due to the facile oxidation of the selenium centre. However, the activity is reduced significantly for compounds having aliphatic substituents. In addition to GPx activity, the compounds also inhibit peroxynitrite-mediated nitration and oxidation reaction of protein and small molecules, respectively. The experimental observations suggest that the antioxidant activity is increased considerably upon substitution of the aromatic group with the benzylic/aliphatic substituents on the nitrogen atoms.

Pd-Catalyzed Hydroborylation of Alkynes: A Ligand Controlled Regioselectivity Switch for the Synthesis of alpha- or beta-Vinylboronates

A ligand controlled selective hydroborylation of alkynes to alpha- or beta-vinylboronates has been developed using a Pd catalyst. The high alpha-selectivity displayed by this reaction can be switched to furnish beta-vinylboronates by altering the ligand from a trialkylphosphine to N-heterocyclic carbene. A variety of terminal alkynes are shown to furnish the corresponding alpha- or beta-vinylboronates in good to excellent selectivity and yield. The mechanistic studies suggest that the solvent is the proton source and bromobenzene functions as an important additive in driving this reaction forward.

Pd-Catalyzed Hydroborylation of Alkynes: A Ligand Controlled Regioselectivity Switch for the Synthesis of alpha- or beta-Vinylboronates

A ligand controlled selective hydroborylation of alkynes to alpha- or beta-vinylboronates has been developed using a Pd catalyst. The high alpha-selectivity displayed by this reaction can be switched to furnish beta-vinylboronates by altering the ligand from a trialkylphosphine to N-heterocyclic carbene. A variety of terminal alkynes are shown to furnish the corresponding alpha- or beta-vinylboronates in good to excellent selectivity and yield. The mechanistic studies suggest that the solvent is the proton source and bromobenzene functions as an important additive in driving this reaction forward.

Sequence specific complexation of b DNA at sites containing g,c base pairs

A series of eight related analogs of distamycin A has been synthesized. Footprinting and affinity cleaving reveal that only two of the analogs, pyridine-2- car box amide-netropsin (2-Py N) and 1-methylimidazole-2-carboxamide-netrops in (2-ImN), bind to DNA with a specificity different from that of the parent compound. A new class of sites, represented by a TGACT sequence, is a strong site for 2-PyN binding, and the major recognition site for 2-ImN on DNA. Both compounds recognize the G•C bp specifically, although A's and T's in the site may be interchanged without penalty. Additional A•T bp outside the binding site increase the binding affinity. The compounds bind in the minor groove of the DNA sequence, but protect both grooves from dimethylsulfate. The binding evidence suggests that 2-PyN or 2-ImN binding induces a DNA conformational change.

In order to understand this sequence specific complexation better, the Ackers quantitative footprinting method for measuring individual site affinity constants has been extended to small molecules. MPE•Fe(II) cleavage reactions over a 10^5 range of free ligand concentrations are analyzed by gel electrophoresis. The decrease in cleavage is calculated by densitometry of a gel autoradiogram. The apparent fraction of DNA bound is then calculated from the amount of cleavage protection. The data is fitted to a theoretical curve using non-linear least squares techniques. Affinity constants at four individual sites are determined simultaneously. The distamycin A analog binds solely at A•T rich sites. Affinities range from 10^(6)- 10^(7)M^(-1) The data for parent compound D fit closely to a monomeric binding curve. 2-PyN binds both A•T sites and the TGTCA site with an apparent affinity constant of 10^(5) M^(-1). 2-ImN binds A•T sites with affinities less than 5 x 10^(4) M^(-1). The affinity of 2-ImN for the TGTCA site does not change significantly from the 2-PyN value. At the TGTCA site, the experimental data fit a dimeric binding curve better than a monomeric curve. Both 2-PyN and 2-ImN have substantially lower DNA affinities than closely related compounds.

In order to probe the requirements of this new binding site, fourteen other derivatives have been synthesized and tested. All compounds that recognize the TGTCA site have a heterocyclic aromatic nitrogen ortho to the N or C-terminal amide of the netropsin subunit. Specificity is strongly affected by the overall length of the small molecule. Only compounds that consist of at least three aromatic rings linked by amides exhibit TGTCA site binding. Specificity is only weakly altered by substitution on the pyridine ring, which correlates best with steric factors. A model is proposed for TGTCA site binding that has as its key feature hydrogen bonding to both G's by the small molecule. The specificity is determined by the sequence dependence of the distance between G's.

One derivative of 2-PyN exhibits pH dependent sequence specificity. At low pH, 4-dimethylaminopyridine-2-carboxamide-netropsin binds tightly to A•T sites. At high pH, 4-Me_(2)NPyN binds most tightly to the TGTCA site. In aqueous solution, this compound protonates at the pyridine nitrogen at pH 6. Thus presence of the protonated form correlates with A•T specificity.

The binding site of a class of eukaryotic transcriptional activators typified by yeast protein GCN4 and the mammalian oncogene Jun contains a strong 2-ImN binding site. Specificity requirements for the protein and small molecule are similar. GCN4 and 2-lmN bind simultaneously to the same binding site. GCN4 alters the cleavage pattern of 2-ImN-EDTA derivative at only one of its binding sites. The details of the interaction suggest that GCN4 alters the conformation of an AAAAAAA sequence adjacent to its binding site. The presence of a yeast counterpart to Jun partially blocks 2-lmN binding. The differences do not appear to be caused by direct interactions between 2-lmN and the proteins, but by induced conformational changes in the DNA protein complex. It is likely that the observed differences in complexation are involved in the varying sequence specificity of these proteins.

Variable-angle electron spectroscopic studies of various polyatomic molecular systems

The complementary techniques of low-energy, variable-angle electron-impact spectroscopy and ultraviolet variable-angle photoelectron spectroscopy have been used to study the electronic spectroscopy and structure of several series of molecules. Electron-impact studies were performed at incident beam energies between 25 eV and 100 eV and at scattering angles ranging from 0° to 90°. The energy-loss regions from 0 eV to greater than 15 eV were studied. Photoelectron spectroscopic studies were conducted using a HeI radiation source and spectra were measured at scattering angles from 45° to 90°. The molecules studied were chosen because of their spectroscopic, chemical, and structural interest. The operation of a new electron-impact spectrometer with multiple-mode target source capability is described. This spectrometer has been used to investigate the spin-forbidden transitions in a number of molecular systems.

The electron-impact spectroscopy of the six chloro-substituted ethylenes has been studied over the energy-loss region from 0-15 eV. Spin-forbidden excitations corresponding to the π → π*, N → T transition have been observed at excitation energies ranging from 4.13 eV in vinyl chloride to 3.54 eV in tetrachloroethylene. Symmetry-forbidden transitions of the type π → np have been oberved in trans-dichloroethyene and tetrachlor oethylene. In addition, transitions to many states lying above the first ionization potential were observed for the first time. Many of these bands have been assigned to Rydberg series converging to higher ionization potentials. The trends observed in the measured transition energies for the π → π*, N → T, and N → V as well as the π → 3s excitation are discussed and compared to those observed in the methyl- and fluoro- substituted ethylenes.

The electron energy-loss spectra of the group VIb transition metal hexacarbonyls have been studied in the 0 eV to 15 eV region. The differential cross sections were obtained for several features in the 3-7 eV energy-loss region. The symmetry-forbidden nature of the ¹A_1g → ¹A_1g, 2t_2g(π) → 3t_2g(π*) transition in these compounds was confirmed by the high-energy, low-angle behavior of their relative intensities. Several low lying transitions have been assigned to ligand field transitions on the basis of the energy and angular behavior of the differential cross sections for these transitions. No transitions which could clearly be assigned to singlet → triplet excitations involving metal orbitals were located. A number of states lying above the first ionization potential have been observed for the first time. A number of features in the 6-14 eV energy-loss region of the spectra of these compounds correspond quite well to those observed in free CO.

A number of exploratory studies have been performed. The π → π*, N → T, singlet → triplet excitation has been located in vinyl bromide at 4.05 eV. We have also observed this transition at approximately 3.8 eV in a cis-/trans- mixture of the 1,2-dibromoethylenes. The low-angle spectrum of iron pentacarbonyl was measured over the energy-loss region extending from 2-12 eV. A number of transitions of 8 eV or greater excitation energy were observed for the first time. Cyclopropane was also studied at both high and low angles but no clear evidence for any spin- forbidden transitions was found. The electron-impact spectrum of the methyl radical resulting from the pyrolysis of tetramethyl tin was obtained at 100 eV incident energy and at 0° scattering angle. Transitions observed at 5.70 eV and 8.30 eV agree well with the previous optical results. In addition, a number of bands were observed in the 8-14 eV region which are most likely due to Rydberg transitions converging to the higher ionization potentials of this molecule. This is the first reported electron-impact spectrum of a polyatomic free radical.

Variable-angle photoelectron spectroscopic studies were performed on a series of three-membered-ring heterocyclic compounds. These compounds are of great interest due to their highly unusual structure. Photoelectron angular distributions using HeI radiation have been measured for the first time for ethylene oxide and ethyleneimine. The measured anisotropy parameters, β, along with those measured for cyclopropane were used to confirm the orbital correlations and photoelectron band assignments. No high values of β similar to those expected for alkene π orbitals were observed for the Walsh or Forster-Coulson-Moffit type orbitals.

Transition metal clusters supported by multinucleating ligand frameworks as models of biological active sites

This dissertation describes efforts to model biological active sites with small molecule clusters. The approach used took advantage of a multinucleating ligand to control the structure and nuclearity of the product complexes, allowing the study of many different homo- and heterometallic clusters. Chapter 2 describes the synthesis of the multinucleating hexapyridyl trialkoxy ligand used throughout this thesis and the synthesis of trinuclear first row transition metal complexes supported by this framework, with an emphasis on tricopper systems as models of biological multicopper oxidases. The magnetic susceptibility of these complexes were studied, and a linear relation was found between the Cu-O(alkoxide)-Cu angles and the antiferromagnetic coupling between copper centers. The triiron(II) and trizinc(II) complexes of the ligand were also isolated and structurally characterized.

Chapter 3 describes the synthesis of a series of heterometallic tetranuclear manganese dioxido complexes with various incorporated apical redox-inactive metal cations (M = Na⁺, Ca²⁺, Sr²⁺, Zn²⁺, Y³⁺). Chapter 4 presents the synthesis of heterometallic trimanganese(IV) tetraoxido complexes structurally related to the CaMn₃ subsite of the oxygen-evolving complex (OEC) of Photosystem II. The reduction potentials of these complexes were studied, and it was found that each isostructural series displays a linear correlation between the reduction potentials and the Lewis acidities of the incorporated redox-inactive metals. The slopes of the plotted lines for both the dioxido and tetraoxido clusters are the same, suggesting a more general relationship between the electrochemical potentials of heterometallic manganese oxido clusters and their “spectator” cations. Additionally, these studies suggest that Ca²⁺ plays a role in modulating the redox potential of the OEC for water oxidation.

Chapter 5 presents studies of the effects of the redox-inactive metals on the reactivities of the heterometallic manganese complexes discussed in Chapters 3 and 4. Oxygen atom transfer from the clusters to phosphines is studied; although the reactivity is kinetically controlled in the tetraoxido clusters, the dioxido clusters with more Lewis acidic metal ions (Y³⁺ vs. Ca²⁺) appear to be more reactive. Investigations of hydrogen atom transfer and electron transfer rates are also discussed.

Appendix A describes the synthesis, and metallation reactions of a new dinucleating bis(N-heterocyclic carbene)ligand framework. Dicopper(I) and dicobalt(II) complexes of this ligand were prepared and structurally characterized. A dinickel(I) dichloride complex was synthesized, reduced, and found to activate carbon dioxide. Appendix B describes preliminary efforts to desymmetrize the manganese oxido clusters via functionalization of the basal multinucleating ligand used in the preceding sections of this dissertation. Finally, Appendix C presents some partially characterized side products and unexpected structures that were isolated throughout the course of these studies.

Selectivity, activity, and stability of ruthenium-carbene based olefin metathesis initiators

The olefin metathesis reaction has found many applications in polymer synthesis and more recently in organic synthesis. The use of single component late metal olefin metathesis catalysts has expanded the scope of the reaction to many new applications and has allowed for detailed study of the catalytic species.

The metathesis of terminal olefins of different steric bulk, different geometry as well as electronically different para-substituted styrenes was studied with the ruthenium based metathesis initiators, trans-(PCy₃)₂Cl₂Ru=CHR, of different carbene substituents. Increasing olefin bulk was found to slow the rate of reaction and trans internal olefins were found to be slower to react than cis internal olefins. The kinetic product of a11 reactions was found to be the alkylidene, rather than the methylidene, suggesting the intermediacy of a 2,4-metallacycle. The observed effects were used to explain the mechanism of ring opening cross metathesis and acyclic diene metathesis polymerization. No linear electronic effects were observed.

In studying the different carbene ligands, a series of ester-carbene complexes was synthesized. These complexes were found to be highly active for the metathesis of olefinic substrates, including acrylates and trisubstituted olefins. In addition, the estercarbene moiety is thermodynamically high in energy. As a result, these complexes react to ring-open cyclohexene by metathesis to alleviate the thermodynamic strain of the ester-carbene ligand. However, ester-carbene complexes were found to be thermolytically unstable in solution.

Thermolytic decomposition pathways were studied for several ruthenium-carbene based olefin metathesis catalysts. Substituted carbenes were found to decompose through bimolecular pathways while the unsubstituted carbene (the methylidene) was found to decompose unimolecularly. The stability of several derivatives of the bis-phosphine ruthenium based catalysts was studied for its implications to ring-closing metathesis. The reasons for the activity and stability of the different ruthenium-based catalysts is discussed.

The difference in catalyst activity and initiation is discussed for the bis-phosphine based and mixed N-heterocyclic carbene/phosphine based ruthenium olefin metathesis catalysts. The mixed ligand catalysts initiate far slower than the bis-phosphine catalysts but are far more metathesis active. A scheme is proposed to explain the difference in reactivity between the two types of catalysts.