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The synthesis of four new oxorhenium(V) complexes containing the “3 + 1” mixed-ligand donor set, ReO(SYS)X (where Y = S, py; X = Cl, Br), is described. All of the complexes tested exhibited selectivity for cathepsin B over K. Most notably, compound 6, ReO(SSS-2,2‘)Br (IC50(cathepsin B) = 1.0 nM), was 260 times more potent against cathepsin B. It was also discovered that complexes containing the same tridentate (SSS) ligand were more potent when the leaving group was bromide versus chloride (e.g., IC50(cathepsin B): ReO(SSS-2,2‘)Cl (4), 8.8 nM; ReO(SSS-2,2‘)Br (6), 1.0 nM). Mechanistic studies with cathepsin B showed that both compounds 2 (ReO(SpyS)(SPhOMe-p)) and 4 were active-site-directed. Compound 2 was determined to be a tight-binding, reversible inhibitor, while compound 4 was a time-dependent, slowly reversible inhibitor. The results described in this paper show that the oxorhenium(V) “3 + 1” complexes are potent, selective inhibitors of cathepsin B and have potential for the treatment of cancer.

The synthesis of several new oxorhenium(V) complexes containing the ‘3 + 1’ mixed-ligand donor set, ReO(SXS)(SR) (where X = S, O, N(R′); R = alkyl, aryl, heterocylce; R′ = H, alkyl, aryl), is described. The X-ray structure for four of these complexes ReO(SN(Ph)S)(SPh) ( 6 ), ReO(SN(CH 2 CH 2 NMe 2 )S)(SPhOMe- p ) ( 10 ), ReO(SOS)(SPh) ( 29 ) and ReO(SOS)(SPhNO 2 - p ) ( 30 ) was determined. The inhibitory activity of all of the oxorhenium(V) complexes reported herein was evaluated against the cysteine proteases cathepsin B and K in vitro. Compound 25 , ReO(SSS)(S-4py) · HCl, was the best inhibitor of the series against cathepsin B with an IC 50 of 10 nM. Several of the complexes exhibited specificity for cathepsin B over K, suggesting that oxorhenium(V) complexes can be designed to be enzyme specific. The results described in this paper show that the oxorhenium(V) ‘3 + 1’ complexes are potent inhibitors of cathepsin B and K, constituting promising potential for the treatment of cancer and osteoporosis, respectively.

In this study a series of Ru I I I complexes, chelated by analogues of ethylenediaminetetraacetic acid (edta) and diethylenetriaminepentaacetic acid (dtpa), were produced and tested for NO scavenging ability. Modifications to the edta and dtpa ligand frameworks were made in an effort to alter the reactivity, aqueous stability and pharmacokinetics of the resulting Ru I I I complexes. The X-ray structure of the nitrosyl complex 38 confirms that the Ru I I I complex 27 reacts with NO to form a linear {Ru-NO} [ 6 ] complex. The nitrosyl complex [C 1 5 H 1 5 N 4 O 1 1 Ru] crystallized in the P2 1 /c space group with a = 12.731(3) A, b = 10.894(2) A, c = 14.241 (3) A, β = 107.320(4)°, V = 1885.6(7)A 3 , and Z = 4. Kinetic studies on the reactions of 14 (k = 2.38×10 6 M - 1 s - 1 ) and 27 (k = 2.30x 10 5 M - 1 s - 1 ) with NO exemplify the difference in chemical properties obtained by ligand framework manipulation. Binding constants of 14 (K B = 5×10 6 M - 1 ) and 27 (K B = 2 × 10 5 M - 1 ) with NO were also measured, indicating the tight binding of NO by the Ru I I I complexes. The activity of the Ru I I I complexes to scavenge nitric oxide was evaluated using RAW264 murine macrophage cells. Ligand analogues of edta that have a pyridine donor as part of the N,N chelate such as 20 and 24 exhibit similar scavenging activity to the parent compound. Ligand analogues of dtpa that have R groups at the central amine in place of the carboxylic acid such as 31, 34, and 37 are also efficient NO scavengers.

Whilst nitric oxide (NO) has emerged as one of the most versatile and ubiquitous molecules in the human body with a diverse range of physiological functions, dysfunction in NO biosynthesis or metabolism has led to the pathogenesis of a number of disease states. A variety of therapeutic strategies have therefore emerged that either reduce or increase endogenous NO levels depending on the disease pathology. The predominant strategy to date to reduce levels of NO is to utilise specific isoform selective inhibitors of nitric oxide synthases, the enzymes responsible for NO biosynthesis. An alternative line of attack, not r elate d to specificity for a particular enzyme, but rather on compartmental localisation and pharmacokinetics, is to re move or sc ave nge the exce ss NO re sponsible for the dise ase pathology. In this regard, a number of NO scavenger molecules have demonstrated pharmacological activity across a broad spectrum of disease states. This review will highlight the rationale behind the development, and the current state of play, of one such class of NO scavengers, complexes of the d-block transition metal ruthenium. Prior to this, a brief overview of the remarkable diversity of NO, both from a chemical and biological viewpoint, will be provided for perspective.

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.

Direct cycloauration of 2-phenoxypyridines with different substituents at the 5-position of the pyridine ring was carried out in an CH3CN/H2O medium, leading to isolation of cycloaurated compounds AuCl2(L) (HL=substituted 2-phenoxypyridine ligand) with alkyl, substituted alkyl, phenyl, halo, ester and amido groups. The preparation of cycloaurated compounds involves the formation of an intermediate AuCl3(HL) via coordination reaction between the pyridine ligand and NaAuCl4 at room temperature and subsequent formation of the Au−C bond at elevated temperature in an CH3CN/H2O medium. The presence of a bulky lipophilic group decreases the yield of cycloaurated compounds and favors the decomposition of the reaction species to Au(0). No coordination reaction was observed for ligands with a strong electron-withdrawing substituent (nitro or nitrile) in the pyridine ring. The ligand having the electron-donating dimethylamino group is oxidized by NaAuCl4 at room temperature. The presence of a thienyl or an acetyl group allowed the isolation of the intermediate AuCl3(HL), but has an adverse effect on the subsequent cycloauration. The result of direct cycloauration of methyl-substituted 2-phenoxypyridine ligands indicated that the presence of a methyl group at the 6-position in the pyridine ring closest to the Au−N(py) bond resulted in poor cycloauration and a decrease in compound stability. The X-ray crystal structure of the cycloaurated compound 25 was determined, depicting a four-coordinate Au atom located in the center of a slightly distorted square.

The compound 5,17-bis(2-chloroacetamido)-25,26,27,28-tetrapropoxycalix[4]arene, 4, was prepared in the cone conformation by the published method. Compound 4 was reacted with α,α‘-m-xylenedithiol an...

Three preorganized metallomacrocycles (9a-c) have been prepared with an immobilized uranyl cation (UO22 +) as an electrophilic center. The macrocyclization in MeOH was accomplished starting from the dialdehyde 7 and the diamines 11a-c using Ba2 + as template ion. Subsequently the Ba2 + complexes 8a-c were reacted with 1 equiv of UO2(OAc)2 to give the uranyl complexes 9a-c in 70 -80 % yield. The association constants of the complexes 9a-c with ammonia, benzylamine, and n-propylamine, determined by 1H NMR spectroscopy in CDCl3, range from 20 to 990 1· mol-1. The highest selectivity for ammonia was observed for 9b (Kass(NH3):Kass (BnNH2) = 33). Molecular mechanics calculations., performed using Quanta/CHARMm, predict that the substitution of the complexed water molecule in the uranyl complex 9a by ammonia is thermodynamically the most favorable.

The preparation of a series of [Ru(III)(tacn)(eta(2)-dtc)(eta(1)-dtc)][PF(6)] (tacn = 1,4,7-triazacyclononane; dtc = dimethyldithiocarbamate, diethyldithiocarbamate, pyrrolidinedithiocarbamate, l-prolinedithiocarbamate, l-prolinemethyl ester dithiocarbamate, l-N-methylisoleucinedithiocarbamate) complexes, 5-11, is described. Complex 5 reacts with NO to form the ruthenium nitrosyl complex 12. A series of [Ru(III)(tacn)(pyc)Cl][PF(6)] (pyc = 2-pyridinecarboxylic acid, 2,4- and 2,6-pyridinecarboxylic acid) complexes, 14-16, were prepared along with [Ru(III)(tacn)(mida)][PF(6)] (mida = N-methyliminodiacetic acid), 13, and [Ru(III)(Hnota)Cl], 17, (Hnota = 1-acetic acid-4,7-bismethylcarboxylate-1,4,7-triazacyclononane). Complexes 5-17 were evaluated for use as NO scavengers in an in vitro assay using RAW264 murine macrophage cells. [Ru(III)(tacn)(eta(2)-dtc)(eta(1)-dtc)][PF(6)] complexes 5-11 are very efficient NO scavengers in this assay.

Reaction of thiophenol with K[Ru(Hedta)Cl] results in the formation of a bis-thiolato-bridged Ru(III)−Ru(III) dimer (II) possessing a Ru−Ru single bond (2.866(1) A) for which the crystal structure is presented.

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 ).

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.

The rates of base hydrolysis of a series of [CoCl(triamine)(diamine)]2+ complexes have been measured using stopped-flow techniques. The triamines used were tacn (1,4,7-triazacyclononane) or dien (3-azapentane-1,5-diamine) and the diamines were en (1,2-diaminoethane), tn (1,3-diaminopropane) or amp (2-aminomethylpyridine). Studies have also been carried out on a corresponding macrobicyclic pentamine 1,5,8,12,15-pentaazabicyclo[10.5.2]nonadecane (L1) where the geometry of the ion is square pyramidal around the cobalt centre. Kinetic parameters [kOH/dm3 mol–1 s–1 at 25 °C (I/mol dm–3), ΔH‡/kJ mol–1, ΔS‡/J K–1 mol–1] in the ligand order (triamine)(diamine) are: (tacn)(en), 9.66 (0.1), 3.66 (1.0), 96.6, 90; (tacn)(tn), 40.6 (0.1), 15.8 (1.0), 94.4, 94; (tacn)(amp), 154 (0.1), 66.7 (1.0), 83.3, 69; ufac-I-(dien)(amp), 334 (0.1), 183 (1.0), 79.6, 66; ufac-II-(dien)(amp), 762 (0.1), 359 (1.0), 73.3, 50; L1, 3 × 103(1.0). Many of the complex ions conform in some measure to the requirements for ready hydrolysis. However, in the last case identified as a result of the initial geometry of the ion, the rate is somewhat lower than anticipated possibly owing to the increased strain involved in the attainment of the trigonal-bipyramidal five-co-ordinate intermediate.