Patrick C. McGowan

Amide Linkage Isomerism As an Activity Switch for Organometallic Osmium and Ruthenium Anticancer Complexes

We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3-5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) <or= min), exhibited significant (32-70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3 >> 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.

Rhodium, Iridium, and Ruthenium Half-Sandwich Picolinamide Complexes as Anticancer Agents

Novel rhodium, iridium, and ruthenium half-sandwich complexes containing (N,N)-bound picolinamide ligands have been prepared for use as anticancer agents. The complexes show promising cytotoxicities, with the presence, position, and number of halides having a significant effect on the corresponding IC50 values. One ruthenium complex was found to be more cytotoxic than cisplatin on HT-29 and MCF-7 cells after 5 days and 1 h, respectively, and it remains active with MCF-7 cells even under hypoxic conditions, making it a promising candidate for in vivo studies.

A one-step synthesis of protected functionalised titanocene dichlorides

Abstract We report a novel, high yield one-step synthesis of water stable and soluble titanocene dichloride dihydrochloride salts from the direct reaction of the neutral amino-substituted cyclopentadienes with TiCl 4 . The following novel complexes have been synthesised: C 5 H 4 (CH 2 ) 2 N(CH 2 ) 5 ] 2 TiCl 2 ( 5 ), [C 5 H 4 CH(CH 2 ) 4 NMe] 2 TiCl 2 ( 6 ), [C 5 H 4 (CH 2 ) 2 N(CH 2 ) 5 ] 2 TiCl 2 ·2HCl ( 7 ), [C 5 H 4 CH(CH 2 ) 4 ] 2 NMeTiCl 2 ·2HCl ( 8 ), [C 5 H 4 (CH 2 ) 2 N(CH 2 ) 5 ] 2 TiMe 2 ( 9 ).

Metallohelices with activity against cisplatin-resistant cancer cells; does the mechanism involve DNA binding?

Enantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy and supported by circular/linear dichroism in solution. Selectivity for 5′-CACATA and 5′-CACTAT segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are stabilised, and remarkably only the Λ metallo-helix enantiomer stabilizes T-shaped 3WJs during gel electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase, and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together these screening and mechanistic results are consistent with the more rigid helices acting via a DNA binding mechanism while the flexible assemblies do not.

Synthesis of η-cyclopentadienyl-polyborane derivatives of molybdenum and tungsten

The reaction of LiBH4 with [Mo(η-C5H4Me)Cl4] gives the dimetallaborane bicapped closo-[{Mo(η-C5H4R)}2B5H9], which has been characterised by X-ray crystallography. The reaction of LiBH4 with [W(η-C5H4R)Cl4], for R = Me, gives closo-[{W(η-C5H4Me)H2}2B3H7] or, for R = Pri, both closo-[{W(η-C5H4Pri)H2}2}B3H7] and nido-[{W(η-C5H4Pri)H3}B4H8]. The reaction between [Mo(η-C5H4Me)(PMe3)2Cl2] and LiBH4 yields bicapped closo-[{Mo(η-C5H4Me)}2B5H9] or nido-[{Mo(η-C5H4Me)(PMe3)H}B4H8], depending on the reaction conditions. Also LiBH4 reacts with [W(PMe3)3Cl4] to give a mixture of nido-[{W(PMe3)2H4}B4H8] and arachno-[{W(PMe3)3H3}B3H8].

Facile synthesis of amino-functionalised cyclopentadienyl sodium compounds and subsequent formation of rhodium complexes: Proton—deuterium exchange for the sodium salts

Synthesis, isolation and characterisation of sodium salts of amino-substituted cyclopentadienyl compounds was carried out for the first time: these can be made on a large scale and stored easily, thus facilitating easy manipulation and applications. Rhodium derivatives, including Rh( η 5 -C 5 H 4 )CH(CH 2 CH 2 ) 2 NMe(coe) 2 (coe = cyclo-octene), were synthesised, of which the crystal structure is reported.

Synthesis, Coordination Chemistry and Bonding of Strong N‐Donor Ligands Incorporating the 1H‐Pyridin‐(2E)‐Ylidene (PYE) Motif

A range of N-donor ligands based on the 1H-pyridin-(2E)-ylidene (PYE) motif have been prepared, including achiral and chiral examples. The ligands incorporate one to three PYE groups that coordinate to a metal through the exocyclic nitrogen atom of each PYE moiety, and the resulting metal complexes have been characterised by methods including single-crystal X-ray diffraction and NMR spectroscopy to examine metal-ligand bonding and ligand dynamics. Upon coordination of a PYE ligand to a proton or metal-complex fragment, the solid-state structures, NMR spectroscopy and DFT studies indicate that charge redistribution occurs within the PYE heterocyclic ring to give a contribution from a pyridinium-amido-type resonance structure. Additional IR spectroscopy and computational studies suggest that PYE ligands are strong donor ligands. NMR spectroscopy shows that for metal complexes there is restricted motion about the exocyclic C-N bond, which projects the heterocyclic N-substituent in the vicinity of the metal atom causing restricted motion in chelating-ligand derivatives. Solid-state structures and DFT calculations also show significant steric congestion and secondary metal-ligand interactions between the metal and ligand C-H bonds.

The Combined Synthesis and Coloration of Poly(lactic acid)

With the continuing depletion of petrochemical feedstocks, it has become necessary to produce new, useful, and environmentally friendly polymers for a sustainable future. Synthesis of a polyester from lactic acid was pioneered by Carothers in 1932 and developed by DuPont. Poly(lactic acid) (PLA) is a linear aliphatic thermoplastic polyester derived from 100 % renewable sources, and the polymer is compostable. The production of PLA uses 20–50% less fossil fuel resources than comparable petroleum-based fibers. PLA is a particularly “green” polymer in terms of sustainability and degradation, two vital components of the cradle-to-grave life cycle. Plants process atmospheric CO2 and water through photosynthesis to make the raw materials from which the building blocks of PLA can be obtained; and composting converts PLA into CO2, water, biomass, humus, and other natural substances (Figure 1). PLA is formed either by direct condensation of lactic acid, or, most effectively, via the cyclic intermediate dimer (lactide) through a catalyzed ring-opening polymerization (ROP) process. Metal alkoxides are the most common catalysts employed in ROP of cyclic esters. Aluminum alkoxides have been shown to give a controlled and living polymerization of lactides through a socalled coordination/insertion mechanism. For a typical textile dyeing process, poly(ethylene terephthalate) and PLA (Figure 1) are initially scoured with detergent and alkali to remove hydrophobic auxiliaries (aids knitting and weaving), and then dyed with disperse dyes in an aqueous dyebath buffered to pH 4.5 using sodium acetate or acetic acid at 130 8C or 115 8C, respectively. To achieve acceptable wash fastness properties (ability of dye to adhere to material), “after-clearing” with reducing agents is employed to remove the excess dye. Reduction after-clearing has a significant detrimental environmental impact because of the strong alkaline conditions, large amounts of water used, and the discharge of high levels of sulfur with the wastewater. 11] There is also concern that effluent from disperse dyeing operations of the reduction after-clearing process contains by-products, particularly aromatic amines from the reduction of azo dyes, that have mutagenic and carcinogenic activity. 13] Herein we report the use of a catalyst containing a chromophore, which will simultaneously carry out the polymerization, and in addition, incorporate the dye, needed to color the material, into the polymer backbone itself—termed the DyeCat process. Thus, the coloration process can achieve high color strength without exposing the fiber to potentially damaging conditions; these are two essential prerequisites for future commercial applications of PLA. As shown in Figure 1, the wet processing stages (preparation, dyeing, finishing) are not required for DyeCat PLA because coloration is achieved through the polymerization process. Hence the consumption of energy, water, chemicals, and time, as well as effluent production are all avoided. Residual catalyst in the polymers can lead to undesirable polymer properties, including discoloration, and removal of the spent catalyst from a polymer is often difficult and Figure 1. Life cycle of PLA for textile applications (Figure adapted from Gross and Kalra).

Functionalised cyclopentadienyl titanium compounds as potential anticancer drugs

A number of new ionic titanocene compounds have been isolated and characterised, which exhibit excellent cytotoxicity against different human tumour cell lines including a defined cisplatin resistant cell line. A range of biological assays have been carried out to determine levels of cytotoxicity and levels of DNA interstrand crosslinking.

Synthesis and reactivity of Group 14 substituted amino-functionalised cyclopentadienyl compounds

Having isolated and characterised a series of sodium amino-functionalised cyclopentadienide salts, a number of Group 14 derivatives have been synthesised and characterised. These have potential as amino-functionalised cyclopentadienyl transfer reagents and a trimethylsilyl derivative has been used from a new type of 1,3-bisfunctionalised ferrocene compound.