Bazı kromonil-2,4-tiyazolidindiyon türevleri ile aldoz redüktaz ve süperoksit dismutazaktivitelerindeki değişiklikler

Abstract

Persistent hyperglycemia in diabetes mellitus (DM) leads to progression of secondary complications, such as neuropathy, nephropathy and retinopathy, which cause irreversible damage once initiated. During states of hyperglycemia, the polyol pathway has increased activity. As a result of the increased polyol pathway activity and the overutilization of NADPH by the enzyme aldose reductase (AR), a number of other homeostatic mechanisms are compromised. In view of the complex metabolic changes induced by hyperglycemia in which AR is critically involved and the prominent role performed by oxidative stress, derivatives endowed with dual activity as AR inhibitors (ARIs) and antioxidant agents could thus represent a promising way forward in the search for useful drugs to treat long-term complications associated with DM. However, many of the clinically tested aldose reductase inhibitors (ARIs) proved to be inadequate as drug candidates because of adverse pharmacokinetics, toxic side effects or low efficacy. For these reasons, nowadays the design of the ARIs which do not cause side effects is still carried on. In our study, AR enzyme was purified from bovine lens tissues. Then, the probable effects of 17 different chromonyl-2,4- thiazolidinedione derivatives on aldose reductase and superoxide dismutase (SOD) enzymes were investigated. Depending upon the results, compounds named 1 and 8 showed the best AR inhibitory activity at the ratio of 52.56% and 58.73 %, respectively. The most activator effect on SOD was found at the ratio of 24.74 % in compound 7

Keywords

• Aldose reductase
• diabetes
• inhibition
• superoxide dismutase
• TZD derivatives

Alterations of aldose reductase and superoxide dismutase activities by some chromonyl-2, 4-thiazolidinedione derivatives

Abstract

Diabetes Mellitus (DM) hastalığındaki uzun süreli hiperglisemi nöropati, nefropati ve retinopati gibi geri-dönüşümsüz sekonder komplikasyonlara neden olmaktadır. Hiperglisemi sırasında polyol yolağının aktivitesi artmaktadır. Artan polyol yolağı aktivitesi ve aldoz redüktaz (AR) tarafından NADPH’ın aşırı tüketimi diğer homeostatik mekanizmaları etkilemektedir. AR’ın dahil olduğu hiperglisemiye bağlı kompleks metabolik değişiklikler ve oksidatif stres sonucunda oluşacak olan diyabetik komplikasyonların tedavisinde hem AR inhibitör etkisi olan hem de antioksidan özelliği bulunan dual etkili ajanların kullanılabilmesi olasılığı, araştırmalar ve tedavi açısından umut vericidir. Bunun yanısıra, klinik olarak denenmiş olan pekçok AR inhibitörünün (ARI) olumsuz farmakokinetikleri, toksik yan etkileri ve yetersiz etkileri nedeni ile ilaç adayı olarak yetersiz oldukları tespit edilmiştir. Bu nedenle, günümüzde hala yan etkisi az olan ARI leri üzerinde çalışmalar devam etmektedir. Çalışmamızda, AR enzimi sığır lenslerinden saflaştırılmıştır. Daha sonra, 17 farklı kromonil-2,4-tiyazolidindiyon türevlerinin AR ve süperoksit dismutaz (SOD) enzim aktiviteleri üzerine olası etkileri incelenmiştir. Sonuçlara göre; 1 ve 8 numaralı bileşikler en iyi ARI aktivitesini sırası ile % 52.56 ve % 58.73 oranları ile göstermiştir. SOD üzerinde ise 7 nolu bileşik % 24.74 oranında aktivatör etki göstermiştir

Keywords

• Aldoz redüktaz
• diyabet
• inhibisyon
• süperoksit dismutaz
• TZD türevleri

References

1. Albuquerque JFC, Albuquerque A, Azevedo CC, Thomasson F, Galdino LS, Chantegrel J (1995): Substituted thiazolidinediones and thioxoimidazolidinones: synthesis, structural study and pharmacological activity. Pharmazie, 50, 87–389.
2. Bradford M (1976): Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 72, 248–254.
3. Brownlee M (2001): Biochemistry and molecular cell biology of diabetic complications. Nature, 414, 813-820.
4. Carbone V, Giglio M, Chung R, Huyton T, Adams J, Maccari R (2010): Structure of aldehyde reductase in ternary complex with a 5-arylidene-2,4-thiazolidinedione aldose reductase inhibitor. Eur J Med Chem, 45, 1140– 1145.
5. Cerelli KJ, Curtis DL, Dunn PH, Nelson PH, Peak TM, Waterbury LD (1986): Anti-inflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids. J Med Chem, 29, 2347-2351.
6. Ceylan-Ünlüsoy M, Verspohl EJ, Ertan R (2010): Synthesis and antidiabetic activity of some new chromonyl- 2,4-thiazolidinediones. J Enz Inhib & Med Chem, 25, 784– 789.
7. Cheng GY, Liu J, Tao MX, Lu CM, Wu GR. (2012): Activity, thermostability and isozymes of superoxide dismutase in 17 edible mushrooms. J Food Comp Analy, 26, 136-143.
8. Chung SSM, Chung SK (2003): Genetic analysis of Aldose Reductase in diabetic complications. Current Med Chem, 10, 1375-1387.

9. El-Kabbani O, Ruiz F, Darmanin C, Chung RPT (2004): Aldose reductase structures: implications for mechanism and inhibition. Cell Mol Life Scien (CMLS), 61, 750-762.
10. Jung HA, Nurul Islam MD, Kwon YS, Jin SE, Son YK, Park JJ (2011): Extraction and identification of three major aldose reductase inhibitors from Artemisia montana. Food Chem Toxicol, 49, 376–384.
11. Kang ES, Iwata K, Ikami K, Ham SA, Kim HJ, Chang KC (2011): Aldose reductase in keratinocytes attenuates cellular apoptosis and senescence induced by UV radiation. Free Rad Biol Med, 50, 680–688.
12. Kostyuk VA, Potapovich AI. (1989): Superoxide-driven oxidation of quercetin and a simple sensitive assay for determination of superoxide dismutase. Biochem Inter, 19, 1117-1124.
13. Ottana R, Maccari R, Giglio M, Del Corso AM, Cappiello U, Mura S (2011): Identification of 5- arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications. Eur J Med Chem, 46, 2797–2806.
14. Özgen O, Ceylan-Ünlüsoy M, Bozdağ-Dündar O, Ertan R, Kendi E (2007): 3-(4-chloro-benzyl)-5-(4-oxo-4H- chromen-3-yl-methylene)-thiazolidine-2,4-dione. Acta Crystal 61, 2355–2356.
15. Rains JL, Jain SK (2011): Oxidative stress, insulin signaling, and diabetes. Free Rad Biol Med, 50, 567–575.
16. Ramana KV (2011): Aldose reductase: New insights for an old enzyme. Biomol Concepts, 2, 103–114.
17. Tammali R, Ramana KV, Srivastava SK (2007): Aldose reductase regulates TNF-a-induced PGE2 production in human colon cancer cells. Cancer Lett, 252, 299–306.
18. Tan SF, Ang KP, Fong YF (1986): (Z) -and (E) -5- Arylmethylenehydantoins: spectroscopic properties and configuration assignement. J Chem Soc Perkin Trans, 12, 1941–1944.
19. Vogeli U, Von Philipsborn W, Nagarajan K, Nair MD (1978): Carbon-13 NMR spectroscopy, part 19. Structures of addition products of acetylenedicarboxylic acid esters with various dinucleophiles. An application of C, H-spin- coupling constants. Helv Chim Acta, 61, 607-617.
20. Yıldırım Ö, Büyükbingol Z (2003): In vivo effect of vitamin C with cobalt on oxidative stress in experimental diabetic rat kidney. Diab Nut Metab, 16, 208-213.
21. Zablockia GJ, Ruzyckia PA, Overturfa MA, Palla S, Reddy GB, Petrasha JM (2011): Aldose reductase- mediated induction of epithelium-to-mesenchymal transition (EMT) in lens. Chem Biol Int, 191, 351–356.
22. Zeng KW, Li J, Dong X, Wang YH, Ma ZZ, Jiang Y, Jin HW, Tu PF (2013): Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways. Toxicol Appl Pharmacol, 273, 159-171.