B-P Coupling: Metal Stabilized Phosphinoborate Complexes.

In an effort to establish B-P coupling reactions without the use of phosphine-borane dehydrocoupling agent, we have developed a new synthetic methodology employing group 8 metal σ-borate complex [{κ3 -H,S,S'-BH2 L2 }Ru{κ3 -H,H,S-BH3 L}] (L=NC5 H4 S), 1. Treatment of 1 with chlorodiphenyl phosphine (PPh2 Cl) yielded 1,5-P,S chelated Ru-dihydridoborate species [PPh2 H{κ3 -H,H,S-BH(OH)L}Ru{κ2 -P,S-(Ph2 P)BH2 L}], 2. The insertion of phosphine moiety (PPh2 ) by the cleavage of 3c-2e σ(Ru… H-B) bonding interaction led to the formation of B-P bond. The κ2 -P,S chelated six-membered ring adopted a boat conformation in complex 2. The heterocycle is made of all different atoms, which is one of the rarest examples of heteroatomic ring systems. Theoretical outcomes demonstrated the electronic insight of B-P coupling and stabilization through transition metal. In order to explore an alternate route of B-P bond formation, we have further explored the reaction of 1 and Ru-bis(dihydridoborate) complex, 5 with secondary phosphine oxide (SPO). Although, thermolysis of 1 with diphenylphosphine oxide yielded analogous σ-borate complex 3, the similar reaction of 5 at room temperature led to the formation of novel phosphinous(III) acid incorporated Ru(σ-borate)(dihydridoborate) complex, 6. In a similar fashion, the reaction of 5 with phosphite ligand generated Ru(σ-borate)(dihydridoborate) complex, 7, which is analogous to 6.

Synthesis, Characterization, DNA/HSA Interaction, and Cytotoxic Activity of a Copper(II) Thiolate Schiff Base Complex and Its Corresponding Water-Soluble Stable Sulfinato-O Complex Containing Imidazole as a Co-ligand.

A Cu(II) thiolato complex [CuL(imz)] (1) (H2L = o-HOC6H4C(H)=NC6H4SH-o) and the corresponding water-soluble stable sulfinato-O complex [CuL'(imz)] (2) (H2L' = o-HOC6H4C(H)=NC6H4S(=O)OH) were synthesized and characterized using physicochemical techniques. Compound 2 is found to be a dimer in the solid state as characterized using single-crystal X-ray crystallography. XPS studies clearly showed the differences in the sulfur oxidation states in 1 and 2. Both compounds are found to be monomers in solution as revealed from their four-line X-band electron paramagnetic resonance spectra in CH3CN at room temperature (RT). 1-2 were tested to assess their ability to exhibit DNA binding and cleavage activity. Spectroscopic studies and viscosity experiments suggest that 1-2 bind to CT-DNA through the intercalation mode having moderate binding affinity (Kb ∼ 104 M-1). This is further supported by molecular docking studies of complex 2 with CT-DNA. Both complexes display significant oxidative cleavage of pUC19 DNA. Complex 2 also showed hydrolytic DNA cleavage. The interaction of 1-2 with HSA revealed that they have strong ability to quench the intrinsic fluorescence of HSA by a static quenching mechanism (kq ∼ 1013 M-1 s-1). This is further complemented by Förster resonance energy transfer studies that revealed binding distances of r = 2.85 and 2.75 nm for 1 and 2, respectively, indicating high potential for energy transfer from HSA to complex. 1-2 were capable of inducing conformational changes of HSA at secondary and tertiary levels as observed from synchronous and three-dimensional fluorescence spectroscopy. Molecular docking studies with 2 indicate that it forms strong hydrogen bonds with Gln221 and Arg222 located near the entrance of site-I of HSA. 1-2 showed potential toxicity in human cervical cancer HeLa cells, lung cancer A549 cells, and cisplatin-resistant breast cancer MDA-MB-231 cells and appeared to be most potent against HeLa cells (IC50 = 2.04 µM for 1 and 1.86 µM for 2). In HeLa cells, 1-2 mediated cell cycle arrest in S and G2/M phases, which progressed into apoptosis. Apoptotic features seen from Hoechst and AO/PI staining, damaged cytoskeleton actin viewed from phalloidin staining, and increased caspase-3 activity upon treatment with 1-2 collectively suggested that they induced apoptosis in HeLa cells via caspase activation. This is further supported by western blot analysis of the protein sample extracted from HeLa cells treated with 2.

Leveraging Torsional and Steric Strains: A Pre-macrocyclization Strategy Enables Conformation-Specific Fullerene Binding in m-Cyclophanes.

Though the chemistry of resorcinarenes is half a century old, the conformationally-locked resorcinarene crowns are generally constructed using hydrogen bonds or covalent tethers. Often, covalent tethering involves extra post-macrocyclization steps involving upper-rim functionalities. We have leveraged the torsional and steric strains through α-substituents of the lower-rim C-alkyl chains and accomplished conformationally-rigid fluorescent m-cyclophane deep-crowns in a predetermined way. The strategy offers a pre-macrocyclization route conserving upper-rim functionalities, an aspect overlooked in resorcinarene chemistry. X-ray structural and computational analyses unveil the cause for conformational rigidity in m-cyclophanes due to α-branching in C-alkyls (linear vs. α-/ß-branched). The conformationally-locked fluorescent deep-crown with a preorganized cavity captures hydrophobic spherical guest C60 in both solution and solid states specifically, when compared to conformationally-dynamic boats, enabling conformation-specific binding.

Mixed Ligand Mononuclear Copper(II) Complex as a Promising Anticancer Agent: Interaction Studies with DNA/HSA, Molecular Docking, and In Vitro Cytotoxicity Studies.

The isolated copper(II) complex [CuL(o-phen)]·H2O (1) [H2L = o-HO-C6H4C(H)=N-C6H4-SH-o, o-phen = 1,10-phenanthroline] was structurally characterized using single-crystal X-ray crystallography. 1 in CH3CN at liquid nitrogen temperature displayed a characteristic monomeric X-band electron paramagnetic resonance spectrum having a tetragonal character with g ∥ = 2.1479 and g ⊥ = 2.0691 and A ∥ ≈ 18.0 mT and A ⊥ ≤ 3.9 mT, respectively. 1 showed a strong binding affinity toward calf thymus DNA as reflected from its intrinsic binding constant (K b = 7.88 × 105 M-1), and its competitive displacement of ethidium bromide suggested an intercalative DNA-binding mode (K app = 1.32 × 106 M-1). This was confirmed from the viscosity study that showed an increase in the viscosity of DNA with an increasing concentration of 1. Complex 1 is highly efficient in promoting oxidative and hydrolytic DNA cleavage (k obs = 1.987 h-1). 1 showed a strong binding affinity with the carrier protein human serum albumin (HSA) (K a = 5.22 × 105 M-1). A high bimolecular quenching constant k q = 2.29 × 1013 M-1s-1 indicated a static quenching mechanism involved in the fluorescence quenching of HSA by 1. Fluorescence resonance energy transfer theory suggested that the distance (r = 3.52 nm) between 1 and HSA is very close. Molecular docking studies suggested that 1 primarily binds to HSA in subdomain IIA. A protein-ligand interaction profiler was used to visualize hydrophobic, hydrogen bonds, and π-cation interactions between HSA and 1. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa and MDA-MB-231 cells showed a significant in vitro anticancer activity of 1 (IC50 2.63 and 2.68 µM, respectively). Nuclear staining assays suggested apoptotic cell death in HeLa cells treated with 1. The effect of 1 on the cytoskeletal actin filaments visualized using phalloidin staining showed extensive destruction of actin filaments. Flow cytometric analysis indicated that 1 inhibits the growth of HeLa cells through cell cycle arrest in the S phase. Western blot analysis showed upregulation in the expression of apoptotic marker proteins caspase 3, p53, and Bax. These results collectively indicate that 1 induces apoptosis by promoting DNA damage and has a high potential to act as an anticancer agent.

Synthesis, Characterization, Crystal Structure, DNA and HSA Interactions, and Anticancer Activity of a Mononuclear Cu(II) Complex with a Schiff Base Ligand Containing a Thiadiazoline Moiety.

A mononuclear Cu(II) complex [Cu(HL)(o-phen)]·H2O (1) [H3L =, o-phen = 1,10-phenanthroline] was isolated from methanol, and its X-ray single-crystal structure was determined. Frozen glass X-band EPR of 1 in dimethylformamide (DMF) at LNT showed a spectrum that is characteristic of a monomeric tetragonal character with g ∥ = 2.164, g ⊥ = 2.087, A ∥ = 19.08 mT, and A ⊥ ≤ 4 mT. Electronic spectroscopic studies using calf thymus DNA (CT-DNA) showed strong binding affinity of 1 as reflected from its intrinsic binding constant (K b) value of 2.85 × 105 M-1. Competitive behavior of 1 with ethidium bromide (EB) displayed intercalative binding of DNA (K app = 1.3 × 106 M-1). The compound displayed significant oxidative cleavage of pUC19 DNA. The interaction between HSA and complex 1 was examined by employing fluorescence and electronic absorption spectroscopic experiments. The secondary and tertiary structures of HSA were found to be altered as suggested by three-dimensional (3D) fluorescence experiments. The affinity of 1 to bind to HSA was found to be strong as indicated from its value of the binding constant (K a = 2.89 × 105 M-1). Intrinsic fluorescence of the protein was found to be reduced through a mechanism of static quenching as suggested from the k q (2.01 × 1013 M-1 s-1) value, the bimolecular quenching constant. The Förster resonance energy transfer (FRET) process may also be accounted for such a high k q value. The r value (2.85 nm) calculated from FRET theory suggested that the distance between complex 1 (acceptor) and HSA (donor) is quite close. Complex 1 primarily bound to HSA in subdomain IIA as suggested by molecular docking studies. IC50 values (0.80 and 0.43 µM, respectively) obtained from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with HeLa and MCF7 cells suggested remarkable in vitro anticancer activity of 1. Nuclear dual staining assays revealed that cell death occurred via apoptosis in HeLa cells and reactive oxygen species (ROS) accumulation caused apoptosis induction. On treatment with a 5 µM dose of 1 in HeLa cells, the cell population significantly increased in the G2/M phase, while it was decreased in G0/G1 and S phases as compared to the control, clearly indicating G2/M phase arrest.

Cooperative B-H and Si-H Bond Activations by κ2-N,S-Chelated Ruthenium Borate Complexes.

Cooperative E-H (E = B, Si) bond activations employing κ2-N,S-chelated ruthenium borate species, [PPh3{κ2-N,S-(NS2C7H4)}Ru{κ3-H,S,S'-H2B(NC7H4S2)2}], (1) are established. Treatment of 1 with BH3·SMe2 yielded the six-membered ruthenaheterocycle [PPh3{κ2-S,H-(BH3NS2C7H4)}Ru{κ3-H,S,S'-H2B(C7H4NS2)2}] (2) formed by a hemilabile ring opening of a Ru-N bond and capturing of a BH3 unit coordinated in an "end-on" fashion. On the other hand, the bulky borane H2BMes shows different reactivity with 1 that led to the formation of the two dihydroborate complexes [{κ3-S,H,H-(NBH2Mes)(S2C7H4)}Ru{κ3-H,S,S'-H2B(C7H4NS2)2}] (3) and [PPh3{κ3-S,H,H-(NBH2Mes)(S2C7H4)}Ru(κ2-N,S-C7H4NS2)] (4), in which H2BMes has been inserted into the Ru-N bond of the initial κ2-N,S-chelated ligand. In an attempt to directly activate hydrosilanes by 1, reactions were carried out with H2SiPh2 that yielded two isomeric five-membered ruthenium silyl complexes, namely [PPh3{κ2-S,Si-(NSiPh2)(S2C7H4)}Ru{κ3-H,S,S'-H2B(C7H4NS2)2}] (5a,b), and the hydridotrisilyl complex [Ru(H){κ2-S,Si-(SiPh2NC7H4S2}3] (6). These complexes were generated by Si-H bond activation with the release of H2 and the formation of N-Si and Ru-Si bonds. When the reaction of 1 was carried out in the presence of PhSiH3, the reaction only produced the analogous complexes [PPh3{κ2-S,Si-(NSiPhH)(S2C7H4)}Ru{κ3-H,S,S'-H2B(C7H4NS2)2}] (5a',b'). Density functional theory (DFT) calculations have been used to probe the bonding modes of boranes/silane with the ruthenium center.

Efficient hydrolytic cleavage of DNA and antiproliferative effect on human cancer cells by two dinuclear Cu(II) complexes containing a carbohydrazone ligand and 1,10-phenanthroline as a coligand.

We report the synthesis, crystal structures and biological activities of two dinuclear Cu(II) complexes [Cu(o-phen)LCu(OAc)] (1) and [Cu(o-phen)LCu(o-phen)](OAc) (2), where o-phen = 1,10-phenanthroline, H3L = o-HOC6H4C(H)=N-NH-C(OH)=N-N=C(H)-C6H4OH-o, and OAc=CH3COO-. Both compounds display strong and broad X-band EPR spectra at RT in their powder state confirming that these are paramagnetic. The intercalative DNA binding of the compounds as revealed from spectrophotometric studies was found to be consistent with the results of fluorescence spectroscopic studies for ethidium bromide displacement assay as well as enhanced viscosity of DNA in the presence of these compounds. The compounds effectively catalyze hydrolytic cleavage of supercoiled pUC19 DNA and show remarkable cytotoxicity toward human lung cancer A549 cell line (IC50 values are 4.34 and 8.46 µM for 1 and 2, respectively) and breast cancer MCF7 cell line (IC50 values are 6.50 and 8.68 µM for 1 and 2, respectively) and are found to be relatively less toxic toward keratinocyte HaCaT normal cell line (IC50 values are 11.19 and 16.01 µM for 1 and 2, respectively). Annexin-V/PI dual staining results analyzed by flow cytometry strongly suggest the induction of apoptotic pathway for the anticancer activity of these complexes. Flow cytometry experiment for cell cycle analysis showed considerable increase in the G2/M phase in both A549 and MCF7 cell lines by these two compounds. On the other hand, compounds 1 and 2 activate reactive oxygen species (ROS) level in A549 cells, but act as scavengers or inhibitors of ROS in MCF7 cell line as analyzed by DCFDA staining using flow cytometry. Two dinuclear Cu(II) complexes exhibit efficient hydrolytic cleavage of DNA and display remarkable cytotoxicity against human lung cancer A549 and breast cancer MCF7cells. The ROS level in A549 cells is activated, but the ROS level in MCF7 cells is decreased in the presence of these complexes. Cell cycle analysis by flow cytometry shows G2/M phase arrest in both these cell lines.

Trithia-diborinane and Bis(bridging-boryl) Complexes of Ruthenium Derived from a [BH3(SCHS)]- Ion.

The field of diborinane is sparsely explored area, and not many compounds are structurally characterized. The room-temperature reaction of [{Cp*RuCl(µ-Cl)}2] (Cp* = η5-C5Me5) with Na[BH3(SCHS)] yielded ruthenium dithioformato [{Cp*Ru(µ,η3-SCHS)}2], 1, and 1-thioformyl-2,6-tetrahydro-1,3,5-trithia-2,6-diborinane complex, [(Cp*Ru){(η2-SCHS)CH2S2(BH2)2}], 2. To investigate the reaction pathway for the formation of 2, we carried out the reaction of [(BH2)4(CH2S2)2], 3, with 1 that yielded compound 2. To the best of our knowledge, it appears that compound 2 is the first example of a ruthenium diborinane complex where the central six-membered ring [CB2S3] adopts the chair conformation. Furthermore, room temperature reaction of 1 with [BH3·thf] resulted in the isolation of agostic-bis(σ-borate) complex, [Cp*Ru(µ-H)2BH(S-CH═S)], 4. Thermolysis of 4 with trace amount of tellurium powder led to formation of bis(bridging-boryl) complex, [{Cp*Ru(µ,η2-HBS2CH2)}2], 5, via dimerization of 4 followed by dehydrogenation. Compound 5 can be considered as a bis(bridging-boryl) species, in which the boryl units are connected to two ruthenium atoms. Theoretical studies and chemical bonding analyses demonstrate the reason for exceptional reactivity and stability of these complexes.

Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig Ketyl-Olefin coupling: the role of HMPA in post-electron transfer steps.

The mechanistic importance of HMPA and proton donors (methanol, 2-methyl-2-propanol, and 2,2,2-trifluoroethanol) on SmI2-initiated 5-exo-trig ketyl-olefin cyclizations has been examined using stopped-flow spectrophotometric studies. In the presence of HMPA, the rate order of proton donors was zero and product studies showed that they had no impact on the diastereoselectivity of the reaction. Conversely, reactions were first-order in HMPA, and the additive displayed saturation kinetics at high concentrations. These results were consistent with HMPA being involved in a rate-limiting step before cyclization, where coordination of the intermediate ketyl to the sterically congested Sm(III)HMPA both stabilizes the intermediate and inhibits cyclization. Liberation of the contact ion pair through displacement by an equivalent of HMPA provides a solvent-separated ion pair releasing the steric constraint to ketyl-olefin cyclization. The mechanism derived from rate studies shows that HMPA is important not only in increasing the reduction potential of Sm(II) but also in enhancing the inherent reactivity of the radical anion intermediate formed after electron transfer through conversion of a sterically congested contact ion pair to a solvent-separated ion pair. The mechanistic complexity of the SmI2-HMPA-initiated ketyl-olefin cyclization is driven by the high affinity of HMPA for Sm(III), and these results suggest that simple empirical models describing the role of HMPA in more complex systems are likely to be fraught with a high degree of uncertainty.