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Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints. We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.

Background A novel, high bioavailability oral, enteric coated tablet formulation of S-adenosylmethionine (MSI-195) has been developed for life science application. The present research reports on a Phase 1 study to (i) determine the safety of single doses of MSI-195 (ii) to determine the dose proportionality of MSI-195 at doses of 400, 800 and 1600 mg (iii) determine the pharmacokinetics of MSI-195 compared with a commercial reference product (SAM-e Complete™) over 24 h and (iv) to determine the effect of food on the pharmacokinetic profile of MSI-195 in human subjects. Methods This study was a pharmacokinetic and safety evaluation of MSI-195 and a commercial comparator broken into two stages. The first stage was an exploratory single ascending dose design of MSI-195 in 8 healthy normal male volunteers. The second stage was a single dose evaluation, targeting 26 male and female volunteers at set doses of MSI-195 and commercial comparator in a cross-over design followed by a food effect study on MSI-195. Plasma samples were collected and assayed for S-adenosylmethionine using a validated HPLC method with MS/MS detection. The main absorption and disposition parameters were calculated using a non-compartmental approach with a log-linear terminal phase assumption. Statistical analysis was based on an ANOVA model or t test as appropriate. Results MSI-195 was found to be generally well tolerated with an adverse event profile similar to the SAM-e Complete™ comparator product. The relative bioavailability of MSI-195 was approximately 2.8-fold higher than SAM-e Complete based on area under the curve (AUC) ratios for the two products and the MSI-195 formulation exposure based on AUC was found to be approximately dose proportional. There was a significant food effect for MSI-195 with a delayed time to maximum absorption Tmax, going from 4.5 h under fasted conditions to 13 h under fed conditions, and area under the curve with food reduced to 55% of that seen under fasting conditions. Conclusions The overall conclusion was that MSI-195 was well tolerated and has markedly higher bioavailability compared with both the SAM-e Complete™ commercial product tested and, on a per mg basis, products reported in other literature. Trial registration ClinicalTrials.gov, identifier NCT04623034. Retrospectively registered Nov 9, 2020.

We conducted a 6-week double-blind, placebo-controlled, augmentation study comparing the efficacy and safety of MSI-195 800 mg (a proprietary formulation of S-adenosylmethionine) or placebo added to ongoing antidepressant medication (ADT) in acutely depressed subjects with Major Depressive Disorder (MDD) who had experienced an inadequate response to their ongoing ADT (The Horizon Study, ClinicalTrials.gov NCT01912196). There were 234 eligible subjects randomized to either MSI-195 (n = 118) or placebo (n = 116). There were no overall statistically significant differences found between MSI-195 added to ongoing ADT compared to placebo on any of 3 depression-rating instruments (HamD 17 , MADRS, IDS-SR 30 ) in the ITT set. MSI-195 was generally safe and well tolerated with predominantly mild gastrointestinal side effects. Post-hoc analyses examined factors that might have affected study outcome. The ITT set was divided into subjects enrolled during the 1st half (first nine months) and 2nd half of the study. MSI-195 added to ongoing ADT was significantly better than placebo on both the HamD 17 and MADRS in the 1st half (p = 0.03 and 0.02 respectively), but not in the 2nd half of the study. Several demographic and clinical characteristics were significantly different between the two study segments including body mass index, pre-randomization symptom severity fluctuation, number of lifetime depressive episodes, and anxious depression sub-type. Thus, the characteristics of the enrolled subjects changed between the 1st and 2nd half of the study. These post-hoc findings highlight the inherent challenges encountered for subject selection in double-blind, placebo controlled trials and compel further investigation of enrollment criteria and moderating factors that affect treatment. The favorable safety profile and clinical benefit observed with MSI-195 in the 1st half of this study warrant further investigation in MDD.

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.

The cysteine proteases of the trypanosomatid parasitic protozoa have been validated as targets for chemotherapy of Chagas' disease and leishmaniasis. Metal complexes of gold, platinum, iridium, palladium, rhodium and osmium have been reported to have activity against a variety of trypanosomatids, but the molecular target of these compounds has not been defined. The activity of gold(III) and palladium(II) cyclometallated complexes, and oxorhenium(V) complexes against mammalian and parasitic cysteine proteases was investigated. All gold(III) complexes (1-6) inhibited cathepsin B with IC(50) values in the range of 0.2-1.4 microM. Of the six palladium compounds, aceto[2,6-bis[(butylthio-kappa S)methyl]phenyl-kappa C]-, (SP-4-3)-palladium(II) (11) was the most potent inhibitor of cathepsin B with an IC(50) of 0.4 microM. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC(50) of 0.009 microM. Six complexes were further tested against the parasite cysteine proteases, cruzain from T. cruzi, and cpB from L. major; the most potent inhibitors were the two rhenium complexes (2(1H)-pyridinethionato-kappa S(2))[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (15) and chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16). The compounds were also evaluated in assays for parasite growth. Two oxorhenium(V) compounds ((p-methoxyphenylthiolato-S)[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (14) and (methanethiolato)[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium (V) (18)) and the palladium compound 11 inhibited T. cruzi intracellular growth, and compound 11 inhibited promastigote growth in three Leishmania species. In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis.

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 preparation of two RuIII polyaminocarboxylate complexes, AMD6245 and AMD6221, and their nitrosyl analogues, AMD6204, AMD6263, and AMD3689, is described. The compounds are characterized by IR, ES-MS, and 13C and 15N NMR spectroscopy where appropriate and cyclic voltammetry. The crystal structures for AMD6245, AMD6263, and AMD3689 are presented. AMD6245 (C10H14N2O9Ru) crystallized in the P21/c space group with a = 8.4382(2) A, b = 8.8304(2) A, c = 17.6321(4) A, β = 99.603°, V = 1295.3(2) A3, and Z = 4. AMD6263 (C10H14N3O10Ru) crystallized in the P21/c space group with a = 9.9043(4) A, b = 13.1144(3) A, c = 12.0914(4) A, β = 100.191°, V = 1545.8(5) A3, and Z = 4. AMD3689 (C14H24.56N4O13.28Ru) crystallized in the P1 space group with a = 8.838(2) A, b = 9.452(3) A, c = 13.419(4) A, α = 78.413(6)°, β = 75.804(6)°, γ = 73.562(6)°, V = 1031.8(5) A3, and Z = 2. The reaction of AMD6245 and AMD6221 with nitric oxide is investigated using EPR spectroscopy and stopped flow kinetics. Upon reaction with NO, a linea...

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.

The preparation of two Ru(III) polyaminocarboxylate complexes, AMD6245 and AMD6221, and their nitrosyl analogues, AMD6204, AMD6263, and AMD3689, is described. The compounds are characterized by IR, ES-MS, and (13)C and (15)N NMR spectroscopy where appropriate and cyclic voltammetry. The crystal structures for AMD6245, AMD6263, and AMD3689 are presented. AMD6245 (C(10)H(14)N(2)O(9)Ru) crystallized in the P2(1)/c space group with a = 8.4382(2) A, b = 8.8304(2) A, c = 17.6321(4) A, beta = 99.603(o), V = 1295.3(2) A(3), and Z = 4. AMD6263 (C(10)H(14)N(3)O(10)Ru) crystallized in the P2(1)/c space group with a = 9.9043(4) A, b = 13.1144(3) A, c = 12.0914(4) A, beta = 100.191(o), V = 1545.8(5) A(3), and Z = 4. AMD3689 (C(14)H(24.56)N(4)O(13.28)Ru) crystallized in the P1 space group with a = 8.838(2) A, b = 9.452(3) A, c = 13.419(4) A, alpha = 78.413(6)(o), beta = 75.804(6)(o), gamma = 73.562(6)(o), V = 1031.8(5) A(3), and Z = 2. The reaction of AMD6245 and AMD6221 with nitric oxide is investigated using EPR spectroscopy and stopped flow kinetics. Upon reaction with NO, a linear, diamagnetic [RuNO](6) complex is formed. The substitution reaction of AMD6245 with NO proceeds with a second-order rate constant of 2.24 x 10(7) M(-1) s(-1) at 7.3 degrees C (pH = 7.4; 50 mM phosphate buffer). The substitution reaction of AMD6221 with NO proceeds with a second-order rate constant of 3 x 10(5) M(-1) s(-1) at 20 degrees C (pH = 7.4; 50 mM phosphate buffered saline). The NO scavenging ability was assessed using a RAW264 murine macrophage assay by measuring the difference in nitrite produced between untreated control cells and treated cells. At 100 microM AMD6245 has [NO(2-)] = 12.5 microM less than the untreated cells and AMD6221 has [NO(2-)] = 37.6 microM less than the untreated cells. There is an insignificant difference in the amount of nitrite produced between AMD6263 or AMD3689 treated cells and untreated cells.

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.

Erratum to ‘‘Metal compounds for the treatment of parasitic diseases” [J. Inorg. Biochem. 102 (2008) 1839–1845] Simon P. Fricker *, Renee M. Mosi , Beth R. Cameron , Ian Baird , Youngbao Zhu , Virginia Anastassov , Jennifer Cox , Patricia S. Doyle , Elizabeth Hansell , Gloria Lau , Jonathan Langille , Micki Olsen , Ling Qin , Renato Skerlj , Rebecca S.Y. Wong , Zefferino Santucci , James H. McKerrow c

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.