Steven C Zammit

Publications (8)29.73 Total impact

• Article: FT23, an orally active antifibrotic compound, attenuates structural and functional abnormalities in an experimental model of diabetic cardiomyopathy.

  Sih Min Tan, Yuan Zhang, Bing Wang, Christina Y R Tan, Steven C Zammit, Spencer J Williams, Henry Krum, Darren J Kelly
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  ABSTRACT: Diabetic cardiomyopathy is characterized by early diastolic dysfunction and structural changes, such as interstitial fibrosis and cardiac hypertrophy. Using the Ren-2 rat model, we sought to investigate the effect of FT23 on the structural and functional changes associated with diabetic cardiomyopathy. Heterozygous Ren-2 rats were rendered diabetic with streptozotocin by tail vein injection. Rats were then treated with FT23 (200 mg/kg per day by gavage twice daily) or vehicle from Week 8 to Week 16 after the onset of diabetes. Echocardiography was performed to assess heart function before the rats were killed and their hearts collected for histological and molecular biological assessment. The antifibrotic effect of FT23 was compared with that of tranilast in neonatal cardiac fibroblasts when stimulated with transforming growth factor (TGF)-β (5 ng/mL) at 30, 50 and 100 umol/L. FT23 exhibited greater inhibition of TGF-β-induced collagen production in neonatal cardiac fibroblasts, as measured by a [(3) H]-proline incorporation assay, compared with its parental compound tranilast. In the in vivo study, FT23 significantly attenuated the increased heart weight : bodyweight ratio in FT23-treated diabetic Ren-2 rats. Diastolic dysfunction, as measured by mitral valve (MV) E/A ratio and MV deceleration time, was also significantly attenuated by FT23. Picrosirius red-stained heart sections revealed that cardiac fibrosis in the diabetic rats was reduced by FT23 compared with that in vehicle-treated rats, with a concomitant reduction in collagen I immunostaining and infiltration of macrophages, as demonstrated by ED1 immunostaining. The results of the present study suggest that FT23 inhibits the activity of TGF-β and attenuates structural and functional manifestations of diastolic dysfunction observed in a model of diabetic cardiomyopathy.
  Clinical and Experimental Pharmacology and Physiology 05/2012; 39(8):650-6. · 1.85 Impact Factor
• Article: FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy.

  Yuan Zhang, Amanda J Edgley, Alison J Cox, Andrew K Powell, Bing Wang, Andrew R Kompa, David I Stapleton, Steven C Zammit, Spencer J Williams, Henry Krum, Richard E Gilbert, Darren J Kelly
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  ABSTRACT: Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm(2); P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05). A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.
  European Journal of Heart Failure 03/2012; 14(5):549-62. · 4.90 Impact Factor
• Article: A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat.

  Richard E Gilbert, Yuan Zhang, Spencer J Williams, Steven C Zammit, David I Stapleton, Alison J Cox, Henry Krum, Robyn Langham, Darren J Kelly
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  ABSTRACT: Locally-active growth factors have been implicated in the pathogenesis of many diseases in which organ fibrosis is a characteristic feature. In the setting of chronic kidney disease (CKD), two such pro-fibrotic factors, transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF) have emerged as lead potential targets for intervention. Given the incomplete organ protection afforded by blocking the actions of TGF-ß or PDGF individually, we sought to determine whether an agent that inhibited the actions of both may have broader effects in ameliorating the key structural and functional abnormalities of CKD. Accordingly, we studied the effects of a recently described, small molecule anti-fibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia), which should have these effects. In the in vitro setting, FT011 inhibited both TGF-ß1 and PDGF-BB induced collagen production as well as PDGF-BB-mediated mesangial proliferation. Consistent with these in vitro actions, when studied in a robust model of non-diabetic kidney disease, the 5/6 nephrectomised rat, FT011 attenuated the decline in GFR, proteinuria and glomerulosclerosis (p<0.05 for all). Similarly, in the streptozotocin-diabetic Ren-2 rat, a model of advanced diabetic nephropathy, FT011 reduced albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Together these studies suggest that broadly antagonising growth factor actions, including those of TGF-ß1 and PDGF-BB, has the potential to protect the kidney from progressive injury in both the diabetic and non-diabetic settings.
  PLoS ONE 01/2012; 7(10):e47160. · 4.09 Impact Factor
• Article: Copper-free palladium-catalyzed Sonogashira and Hiyama cross-couplings using aryl imidazol-1-ylsulfonates

  Steven J. Shirbin, Berin A. Boughton, Steven C. Zammit, Shannon D. Zanatta, Sebastian M. Marcuccio, Craig A. Hutton, Spencer J. Williams
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  ABSTRACT: Aryl imidazylates are effective electrophilic partners in copper-free palladium-catalyzed Hiyama and Sonogashira cross-coupling reactions. The Sonogashira cross-coupling of estron-3-yl imidazylate afforded the corresponding phenylacetylene derivative in excellent yield.
  Tetrahedron Letters 01/2010; 51(22):2971-2974. · 2.68 Impact Factor
• Source

  Available from: Darren J Kelly

  Article: Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates.

  Steven C Zammit, Alison J Cox, Renae M Gow, Yuan Zhang, Richard E Gilbert, Henry Krum, Darren J Kelly, Spencer J Williams
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  ABSTRACT: Tranilast is an anti-inflammatory drug in use for asthma and atopic dermatitis. In studies over the last decade it has been revealed that tranilast can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. We report a structure-activity study aimed at optimizing the antifibrotic activity of tranilast. A series of cinnamoyl anthranilates were prepared and assessed for their ability to prevent TGF-beta-stimulated production of collagen in cultured renal mesangial cells. We reveal derivatives with improved potency and reduced cellular toxicity relative to tranilast. 3-Methoxy-4-propargyloxycinnamoyl anthranilate reduces albuminuria in a rat model of progressive diabetes, and thus has potential as an innovative treatment for diabetic nephropathy.
  Bioorganic & medicinal chemistry letters 10/2009; 19(24):7003-6. · 2.65 Impact Factor
• Article: 'Click' cycloaddition catalysts: copper(I) and copper(II) tris(triazolylmethyl)amine complexes.

  Paul S Donnelly, Shannon D Zanatta, Steven C Zammit, Jonathan M White, Spencer J Williams
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  ABSTRACT: The CuI complex of the 'click' ligand tris(benzyltriazolylmethyl)amine is an unusual dinuclear dication with one triazole unit bridging two metal centers, and is an effective catalyst for the 'click' cycloaddition reaction.
  Chemical Communications 07/2008; · 6.17 Impact Factor
• Article: Enantiospecific synthesis of the heparanase inhibitor (+)-trachyspic acid and stereoisomers from a common precursor.

  Steven C Zammit, Vito Ferro, Edward Hammond, Mark A Rizzacasa
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  ABSTRACT: The total synthesis of natural (+)-trachyspic acid and its enantiomer is described starting from a common 2-deoxy-d-ribose derivative. The synthesis of the corresponding C3 epimers from the same starting material is also described. Each stereoisomer was assayed for heparanase inhibition.
  Organic & Biomolecular Chemistry 10/2007; 5(17):2826-34. · 3.70 Impact Factor
• Article: Enantiospecific synthesis of (-)-trachyspic acid.

  Steven C Zammit, Jonathan M White, Mark A Rizzacasa
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  ABSTRACT: The enantiospecific synthesis of (-)-trachyspic acid () is presented. This has allowed for the assignment of the absolute configuration of natural (+)-trachyspic acid as 3S,4S,6S.
  Organic & Biomolecular Chemistry 07/2005; 3(11):2073-4. · 3.70 Impact Factor