-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of Medicinal Chemistry 09/2006; 49(17):5262-72. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 related to specificity for a particular enzyme, but rather on compartmental localisation and pharmacokinetics, is to remove or scavenge the excess NO responsible for the disease 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.
Current Topics in Medicinal Chemistry 02/2004; 4(15):1585-603. · 4.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We tested whether nitric oxide scavenging with a ruthenium-based compound (AMD6221) would improve hemodynamics and alter nitric oxide synthase and matrix metalloproteinase activities in a canine model of cardiopulmonary bypass.
Dogs were randomized to either cardiopulmonary bypass (n = 12) or control (n = 12) groups. They were further randomized to receive a continuous infusion of AMD6221 or placebo. Cardiopulmonary bypass was maintained for 90 minutes, and then, 4 hours later, dogs were killed. Cardiac, lung, and brain sections were snap frozen in liquid nitrogen for determination of nitric oxide synthase, matrix metalloproteinase 2, and matrix metalloproteinase 9 activities.
After cardiopulmonary bypass, 3 of 6 placebo-treated (cardiopulmonary bypass-placebo) and 0 of 6 AMD6221-treated (cardiopulmonary bypass-6221) animals required phenylephrine infusion to maintain a predetermined blood pressure (P <.05). Total fluid administration was lower in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (983 +/- 134 vs 1617 +/- 254 mL, respectively; P <.005). After cardiopulmonary bypass, matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in the lung, left ventricle, and left atrium were decreased in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (P <.05). Ca(2+)-independent nitric oxide synthase activity and matrix metalloproteinase 2 activity in the brain were also lower (P <.05) in the cardiopulmonary bypass-SCV group. Finally, neutrophil expression of CD18, an adhesion complex, was lower at 4 hours after cardiopulmonary bypass in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (38 +/- 27 vs 81 +/- 11; P <.05).
We found that (1) infusion of an nitric oxide scavenger, AMD6221, was associated with improved predefined hemodynamics; (2) cardiopulmonary bypass increased activities of Ca(2+)-independent nitric oxide synthase and matrix metalloproteinases in multiple organs; and (3) AMD6221 could ameliorate the increased generation of nitric oxide and increased matrix metalloproteinase activities.
Journal of Thoracic and Cardiovascular Surgery 03/2003; 125(3):661-8. · 3.41 Impact Factor
-
Galen M Pieper,
Allan M Roza,
Mark B Adams,
Gail Hilton,
Mary Johnson,
Christopher C Felix,
Bal Kampalath,
Marilyn Darkes,
Yangsheng Wanggui, Beth Cameron,
Simon P Fricker
[show abstract]
[hide abstract]
ABSTRACT: Nitric oxide (NO) derived from the up-regulation of inducible NO synthase (iNOS) is believed to play an important role in organ rejection. In experimental models of acute cardiac transplant rejection (i.e., without immunosuppression), treatment using NOS inhibitors to prevent acute rejection have yielded conflicting results. This is most likely due to potential inhibition of constitutive NOS. Accordingly, agents that trap NO directly may have some advantage. In the current study, we evaluated the actions of a ruthenium-based NO scavenger, AMD6221, to inhibit the nitrosylation of myocardial protein and to prolong cardiac allograft survival in a model of acute cardiac transplant rejection (without immunosuppression). In addition, we evaluated the efficacy of AMD6221 used in combination with low-dose cyclosporine (CsA) (i.e., a model of delayed graft rejection). Heterotopic abdominal cardiac transplantation was performed using rat strains with disparities at major and minor histocompatibility loci. Grafts were harvested on postoperative day 6 for histologic examination or analysis of myocardial protein nitrosylation using electron paramagnetic resonance (EPR) spectroscopy. Other animals were monitored twice daily to determine rejection times. Plasma was also taken at postoperative day 6 for determining the concentration of NO by-products (nitrate plus nitrite). Treatment with AMD6221 either prolonged graft survival and/or caused a marked decrease in myocardial nitrosylprotein formation as determined by EPR spectroscopy. In vivo scavenging of NO by AMD6221 was verified by high-performance liquid chromatography analysis of nitrosylated-drug in plasma samples. Low-dose CsA given alone or in combination with AMD6221 completely blocked formation of myocardial nitrosylprotein complexes. Whereas low-dose CsA alone prolonged graft survival, combination therapy with CsA plus AMD6221 produced a synergistic effect on graft survival. These studies indicate that treatment with a ruthenium-based NO scavenger, such as AMD6221, may be an effective regimen used alone or in combination with CsA to protect myocardial proteins from posttranscriptional modification and to prolong cardiac graft survival.
Journal of Cardiovascular Pharmacology 04/2002; 39(3):441-8. · 2.29 Impact Factor
