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Polypyridyl-Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition

We report a series of copper(II) artificial metallo-nucleases (AMNs) and demonstrate their DNA damaging properties and in-vitro cytotoxicity against human-derived pancreatic cancer cells. The compounds combine a tris-chelating polypyridyl ligand, di-(2-pycolyl)amine (DPA), and a DNA intercalating phenanthrene unit. Their general formula is Cu-DPA-N,N' (where N,N'=1,10-phenanthroline (Phen), dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ)). Characterisation was achieved by X-ray crystallography and continuous-wave EPR (cw-EPR), hyperfine sublevel correlation (HYSCORE) and Davies electron-nuclear double resonance (ENDOR) spectroscopies. The presence of the DPA ligand enhances solution stability and facilitates enhanced DNA recognition with apparent binding constants (K_app) rising from 10⁵ to 10⁷ m ⁻¹ with increasing extent of planar phenanthrene. Cu-DPA-DPPZ, the complex with greatest DNA binding and intercalation effects, recognises the minor groove of guanine–cytosine (G-C) rich sequences. Oxidative DNA damage also occurs in the minor groove and can be inhibited by superoxide and hydroxyl radical trapping agents. The complexes, particularly Cu-DPA-DPPZ, display promising anticancer activity against human pancreatic tumour cells with in-vitro results surpassing the clinical platinum(II) drug oxaliplatin.     

Enabling drug discovery project decisions with integrated computational chemistry and informatics

Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training.     

Synthesis,structural characterization and alcohol oxidation activity of a new mononuclear manganese(II) complex

A manganese(II) complex of 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz) has been synthesized and characterized by single-crystal X-ray diffraction, elemental analyses, IR, and UV–Vis spectroscopic techniques. Oxidation of alcohols to their corresponding aldehydes and ketones was conducted by this catalyst using oxone (2KHSO₅·KHSO₄·K₂SO₄) as an oxidant under biphasic reaction conditions (CH₂Cl₂/H₂O) and tetra-n-butylammonium bromide as phase transfer agent under air at room temperature. Easy preparation, mild reaction conditions, high yields of the products, short reaction times, no further oxidation to the corresponding carboxylic acids, high selectivity and inexpensive reagents make this catalytic system a useful oxidation method for aliphatic and benzylic alcohols.     

Preparation of PtSnSb/C by an alcohol reduction process for direct ethanol fuel cell (DEFC)

PtSn/C and PtSnSb/C electrocatalysts (20 wt.% metal loading) were prepared by an alcohol reduction process using H₂PtCl₆.6H₂O, SnCl₂.2H₂O, and Sb(OOCCH3) as metal sources, ethylene glycol as solvent and reducing agent, and Vulcan XC72 as carbon support. The electrocatalysts were characterized by energy dispersive X-ray analysis, X-ray diffraction, and transmission electron microscopy, while that the performance for ethanol oxidation was investigated by cyclic voltammetry and chronoamperommetry (chrono) at room temperature. The diffractograms of the PtSn/C and PtSnSb/C electrocatalysts showed four peaks associated to Pt face-centered cubic structure and two peaks that were related to a SnO₂ phase. For PtSb/C and PtSnSb/C electrocatalysts, no Sb (antimony) peaks corresponding to a metallic antimony or antimony oxide phases were observed. Transmission electron microscopy images showed that the metal particles were homogeneously distributed over the support. The PtSnSb/C (50:45:05) electrocatalyst showed an increase of performance for ethanol oxidation in relation to PtSn/C electrocatalyst at room temperature. In the tests at 100 °C on a single cell of a direct ethanol fuel cell, the maximum power density of PtSnSb/C (50:45:05) electrocatalyst was slightly higher than that of PtSn/C electrocatalyst.     

Imidazolium ylides from a conjugate addition-proton transfer route and their cycloaddition reactions

4,5-Dihydroimidazolium ylides formed by conjugate addition-proton transfer from dihydroimidazoles and doubly-activated electron-deficient alkenes afford 2:1 cycloadducts in a one-pot process wherein the alkene also acts as a dipolarophile.     

A Click Chemistry Approach to Developing Molecularly Targeted DNA Scissors

Nucleic acid click chemistry was used to prepare a family of chemically modified triplex forming oligonucleotides (TFOs) for application as a new gene-targeted technology. Azide-bearing phenanthrene ligands—designed to promote triplex stability and copper binding—were ‘clicked’ to alkyne-modified parallel TFOs. Using this approach, a library of TFO hybrids was prepared and shown to effectively target purine-rich genetic elements in vitro. Several of the hybrids provide significant stabilisation toward melting in parallel triplexes (>20 °C) and DNA damage can be triggered upon copper binding in the presence of added reductant. Therefore, the TFO and ‘clicked’ ligands work synergistically to provide sequence-selectivity to the copper cutting unit which, in turn, confers high stabilisation to the DNA triplex. To extend the boundaries of this hybrid system further, a click chemistry-based di-copper binding ligand was developed to accommodate designer ancillary ligands such as DPQ and DPPZ. When this ligand was inserted into a TFO, a dramatic improvement in targeted oxidative cleavage is afforded.     

Crystal Structure of Bis(5,17-dihydroxy-3,7,15,19,25,26-hexa-azatricyclo(19.3.1.19,13)hexacosa-1(25),2,7,9(26),10,12,14,19,21,23-decaene-μ1,2-perchlorato barium) diperchlorate: a Schiff-Base Macrocyclic Complex Derived from 2,6-Diformylpyridine and 1,3-Diaminopropan-2-ol

Abstract  

The title complex, [Ba(L1)(μ_1,2-ClO₄)]₂(ClO₄)₂ (where L1 = 5,17-dihydroxy-3,7,15,19,25,26-hexa-azatricyclo(19.3.1.19,13)hexacosa-1(25),2,7,9(26),10,12,14,19,21,23-decaene), was synthesised by a Schiff base condensation of 2,6-diformylpyridine with 1,3-diaminopropan-2-ol in dry methanol using barium(II) as template ion. The complex was characterised by IR, ¹H NMR, mass spectrometry, elemental analysis and X-ray crystallography. The structure was solved in the triclinic space group P [`\text1] {\bar{\text{1}}} with a = 8.4587(9), b = 8.7360(9), c = 17.7722(19) ?, α = 79.786(2), β = 88.780(2), γ = 83.048(2)°, V = 1283.0(2) ?³, Z = 1 and R1 = 0.0433. The macrocycle is folded and the complex dimerises via perchlorate anions which bridge the barium ions, and this interaction is supported by hydrogen bonding between neighbouring alcohol groups. The dimers are further linked into chains via intermolecular O–H···OClO₃ hydrogen bonds.