Beth R. Cameron

Inhibition of the cathepsin cysteine proteases B and K by square-planar cycloaurated gold(III) compounds and investigation of their anti-cancer activity.

Gold(III) compounds have been examined for potential anti-cancer activity. It is proposed that the molecular targets of these compounds are thiol-containing biological molecules such as the cathepsin cysteine proteases. These enzymes have been implicated in many diseases including cancer. The catalytic mechanism of the cathepsin cysteine proteases is dependent upon a cysteine at the active site which is accessible to the interaction of thiophilic metals such as gold. The synthesis and biological activity of square-planar six-membered cycloaurated Au(III) compounds with a pyridinyl-phenyl linked backbone and two monodentate or one bidentate leaving group is described. Gold(III) cycloaurated compounds were able to inhibit both cathepsins B and K. Structure/activity was investigated by modifications to the pyridinyl-phenyl backbone, and leaving groups. Optimal activity was seen with substitution at the 6 position of the pyridine ring. The reversibility of inhibition was tested by reactivation in the presence of cysteine with a bidentate thiosalicylate compound being an irreversible inhibitor. Five compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The thiosalicylate compound was tested in vivo against the HT29 human colon tumor xenograft model. A modest decrease in tumor growth was observed compared with the untreated control tumor.

Unique chemistry of amino acid dithiocarbamates with Ru(III) bis-β-diketonates

Abstract The complexation chemistry of several dithiocarbamates (dtc) (KS2CProOMe, KS2CProK, KNMeIleK) with [Ru(β-diketonato)2(MeCN)2][CF3SO3] (β-diketonato=acac (2,4-pentanedionato) and dpac (1,3-diphenyl-1,3-propanedionato)) was investigated. It was discovered that the dtc underwent some unusual and unprecedented CS2-elimination chemistry to yield chelated imino or amino acidato Ru(III) complexes. For the proline case, both the KS2CProOMe and KS2CProK dtc yielded two products, the chelated dithiocarbamato complexes Ru(β-diketonato)2(dtc) (dtc=S2CProOMe or S2CProK) and the CS2-eliminated imino prolinato complexes Ru(β-diketonato)2(Pro-H2) (β-diketonato=acac (10) and dpac (14)) for which the crystal structures have been determined. For the N-methylisoleucine case, KS2CNMeIleK yielded only the CS2-eliminated amino N-methylisoleucinato complexes Ru(β-diketonato)2(NMeIle). The X-ray structure for Ru(acac)2(NMeIle) (16) was determined. The direct reaction of the amino acids (Pro or NMeIle) with [Ru(β-diketonato)2(MeCN)2][CF3SO3] yielded [Ru(dpac)2(Pro)]2 and [Ru(acac)2(NMeIle)]2, the first examples of paramagnetic μ-amino acidato bridged Ru(III) dimers which could be converted to their corresponding chelated amino acidato monomeric complexes upon treatment with base. The formal potentials of all of the Ru(III) complexes reported were determined by cyclic voltammetry.

Bis(amido)calix[4]arenes in the pinched cone conformation as tuneable hydrogen-bonding anion receptors

Calix[4]arene units functionalized at the 1,3-positions of the upper rim with amido groups, –NHC(O)X, act as neutral, hydrogen-bonding receptors for hydrogen sulfate, dihydrogen phosphate, acetate, benzoate, nicotinate, oxalate, terephthalate, isophthalate and fumarate with binding strength and selectivity tunable by varying the electron-withdrawing ability of the terminal substituent X (X = CH 2 Cl, CHCl 2 , CCl 3 ).

Calixarene metalloreceptor. Upper-rim functionalized calix[4]arenas containing an organopalladium binding site

Calix[4]arene units functionalized at the 1,3-positions of the upper rim with an organopalladium binding site demonstrate simultaneous first- and second-sphere coordination of a substrate through binding to the palladium centre and interaction within the hydrophobic site provided by the calixarene unit.