[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPARγ ligand

• Authors: Marta Soltesova Prnova , Magdalena Majekova , Ivana Milackova , Beatriz Díez-Dacal , Dolores Pérez-Sala , Muserref Ceyhan , Sreeparna Banerjee , Milan Stefek
• Languages of publication: EN

Abstracts

EN

Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl]acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPARγ. Aldose reductase inhibition by 1 was characterized by IC50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPARγ, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes.

Keywords

EN

aldose reductase inhibitor; PPARγ ligand; diabetes; indole

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2015
• Volume: 62
• Issue: 3
• Pages: 523-528

Dates

published

2015

received

2014-12-05

revised

2015-08-21

accepted

2015-08-25

(unknown)

2015-09-08

Contributors

author

Marta Soltesova Prnova

• Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia

author

Magdalena Majekova

• Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia

author

Ivana Milackova

• Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia

author

Beatriz Díez-Dacal

• Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain

author

Dolores Pérez-Sala

• Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain

author

Muserref Ceyhan

• Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

author

Sreeparna Banerjee

• Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

author

Milan Stefek

• Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia

References

• Alexiou P, Pegklidou K, Chatzopoulou M, Nicolaou I, Demopoulos VJ (2009) Aldose reductase enzyme and its implication to major health problems of the 21(st) century. Curr Med Chem 16: 734-752.
• Barski OA, Gabbay KH, Grimshaw CE, Bohren KM (1995) Mechanism of human aldehyde reductase: characterization of the active site pocket. Biochemistry 34: 11264-11275. Doi: 10.1021/bi00035a036.
• Chatzopoulou M, Alexiou P, Kotsampasakou E, Demopoulos VJ (2012) Novel aldose reductase inhibitors: a patent survey (2006-present). Expert Opin Ther Pat 11: 1303-1323.
• Congreve M, Carr R, Murray C, Jhoti H (2003) A 'rule of three' for fragment-based lead discovery? Drug Discovery Today 8: 876-877.
• Cook PN, Ward WH, Petrash JM, Mirrlees DJ, Sennitt CM, Carey F, Preston J, Brittain DR, Tuffin DP, Howe R (1995) Kinetic characteristics of zeneca ZD5522, a potent inhibitor of human and bovine lens aldose reductase. Biochem Pharmacol 49: 1043-1049.
• Costantino L, Rastelli G, Gamberini MC, Barlocco D (2000) Pharmacological approaches to the treatment of diabetic complications. Expert Opin Ther Pat 10: 1245-1262.
• Costantino L, Rastelli G, Gamberini MC, Vinson JA, Bose P, Iannone A, Staffieri M, Antolini L, Del Corso A, Mura U, Albasini A (1999) 1-Benzopyran-4-one Antioxidants as Aldose Reductase Inhibitors. J Med Chem 42: 1881-1893.
• DeRuiter J, Borne RF, Mayfield CA (1989) N- and 2-substituted N-(phenylsulfonyl) glycines as inhibitors of rat lens aldose reductase. J Med Chem 32: 145-151.
• DeRuiter J, Mayfield CA (1990) Inhibitory activity and mechanism of inhibition of the N-[[(4-benzoylamino)phenyl]sulfonyl] amino acid aldose reductase inhibitors. Biochem Pharmacol 40: 2219-2226.
• Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83: 803-812.
• Haraguchi H, Hayashi R, Ishizu T, Yagi A (2003) A flavone from Manilkara indica as a specific inhibitor against aldose reductase in vitro. Planta Med 69: 853-855.
• Hayman S, Kinoshita J (1965) Isolation and Properties of Lens Aldose Reductase. J Biol Chem 240: 877-882.
• Hotta N (1995) New approaches for treatment in diabetes: Aldose reductase inhibitors. Biomed Pharmacother 49: 232-243.
• Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D, Schneider TR, Joachimiak A, Podjarny A (2004) Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. Proteins 55: 792-804.
• Juskova M, Majekova M, Demopoulos V, Stefek M (2011) Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship. Gen Physiol Biophys 30: 342-349.
• Krieger E, Koraimann G, Vriend G (2002) Increasing the precision of comparative models with YASARA NOVA - a self-parameterizing force field. Proteins [Online] 47: 393-402. Available at: www.yasara.org.
• Luker T, Bonnert R, Brough S, Cook AR, Dickinson MR, Dougall I, Logan C, Mohammed RT, Paine S, Sanganee HJ, Sargent C, Schmidt JA, Teague S, Thom S (2011) Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981. Bioorg Med Chem Lett 21: 6288-6292.
• Mahindroo N, Huang CF, Peng YH, Wang CC, Liao CC, Lien TW, Chittimalla SK, Huang WJ, Chai CH, Prakash E, Chen CP, Hsu TA, Peng CH, Lu IL, Lee LH, Chang YW, Chen WC, Chou YC, Chen CT, Goparaju CM, Chen YS, Lan SJ, Yu MC, Chen X, Chao YS, Wu SY, Hsieh HP (2005) Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities. J Med Chem 48: 8194-8208.
• Mahindroo N, Peng YH, Lin CH, Tan UK, Prakash E, Lien TW, Lu IL, Lee HJ, Hsu JT, Chen X, Liao CC, Lyu PC, Chao YS, Wu SY, Hsieh HP (2006) Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists. J Med Chem 49: 6421-6424.
• Mahindroo N, Wang CC, Liao CC, Huang CF, Lu IL, Lien TW, Peng YH, Huang WJ, Lin YT, Hsu MC, Lin CH, Tsai CH, Hsu JT, Chen X, Lyu PC, Chao YS, Wu SY, Hsieh HP (2006) Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies. J Med Chem 49: 1212-1216.
• Miyamoto S (2002) Recent advances in aldose reductase inhibitors: potential agents for the treatment of diabetic complications. Expert Opin Ther Pat 12: 621-631.
• Mylari BL, Armento SJ, Beebe DA, Conn EL, Coutcher JB, Dina MS, O'Gorman MT, Linhares MC, Martin WH, Oates PJ, Tess DA, Withbroe GJ, Zembrowski WJ (2003) A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one. J Med Chem 46: 2283-2286.
• Rees-Milton KJ, Jia Z, Green NC, Bhatia M, El-Kabbani O, Flynn TG (1998) Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities. Arch Biochem Biophys 355: 137-144.
• Sangster J (1997) In octanol-water partition coefficients: Fundamentals and Physical Chemistry. vol. 2. John Willey & Sons, England.
• Shao Y, Molnar LF, Jung Y, Kussmann J, Ochsenfeld C, Brown ST, Gilbert ATB, Slipchenko LV, Levchenko SV, O'Neill DP, et al (2006) Advances in methods and algorithms in a modern quantum chemistry program package. Phys Chem Chem Phys 8: 3172-3191.
• da Silva FM, dos Santos JC, Campos JL, Mafud AC, Polikarpov I, Figueira AC, Nascimento AS (2013) Structure-based identification of novel PPAR gamma ligands. Bioorg Med Chem Lett 23: 5795-5802.
• Srivastava SK, Ramana KV, Bhatnagar A (2005) Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 26: 380-392.
• Stefek M, Snirc V, Djoubissie PO, Majekova M, Demopoulos V, Rackova L, Bezakova Z, Karasu C, Carbone V, El-Kabbani O (2008) Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: Synthesis, activity, partitioning, and molecular modelling. Bioorg Med Chem 16: 4908-4920.
• Tang WH, Martin KA, Hwa J (2012) Aldose reductase, oxidative stress, and diabetes mellitus. Front Pharmacol 3: 87.
• Terashima H, Hama K, Yamamoto R, Tsuboshima M, Kikkawa R, Hatanaka I, Shigeta YJ (1984) Effects of a new aldose reductase inhibitor on various tissues in vitro. Pharm Exp Ther 229: 226-230.
• Van Zandt MC, Doan B, Sawicki DR, Sredy J, Podjarny AD (2009) Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications. Bioorg Med Chem Lett 19: 2006-2008.
• Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD (2005) Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications. J Med Chem 48: 3141-3152.
• Verheij HJ (2006) Leadlikeness and structural diversity of synthetic screening libraries. Molecular Diversity 10: 377-388.
• Walker H, Testa B (2009) Drug bioavailability: estimation of solubility, permeability, absorption and bioavailability. WILEY-vch Verlag GmbH & Co. KGaA Weinheim.
• Yabe-Nishimura C (1998) Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications. Pharm Rev 50: 21-33.

Identifiers

DOI

10.18388/abp.2014_953