The aldehyde reductase AKR A

The aldehyde reductase (AKR1A1) and aldose reductase (AKR1B1) belong to aldo-ketoreductase (AKR) superfamily catalyzing the reduction of corresponding aldehydes and ketones involved. Both the closely related enzymes AKR1A1 and AKR1B1 have 65% structural similarity and differ only at the active site. While AKR1B1 is mainly involved in polyol pathway, AKR1A1 is responsible for reductive detoxification of reactive aldehydes, and metabolizes methyl glyoxal and 3-deoxyglucosone which have role in the formation of toxic glycation end products [26], [27]. Aldehye reductase (AKR1A1) being a member of AKR superfamily has significant role in various biological processes such as regulation of proinflammatory response through the reduction of aldehyde phospholipids [28]. Since many aldose reductase inhibitors (ARIs) has been reported, but none of them get success in advance clinical trial, and so far only one make been marketed; Epalrestat, ONO Pharmaceutical, Osaka, Japan [28]. Use of isolated natural products would be potentially beneficial to find good lead as ARIs Evidence showed that the inhibition of polyol pathway is an attractive challenge to alleviate the diabetic complications and aldose reductase inhibitors (ARIs) can play significant role in that. A large number of ARIs mainly hydantoin and carboxylic Colistin Methanesulfonate sodium salt derivatives have entered into clinical trials, the only marketed drug is Epalrestat which is rhodanine based [26], [29]. During clinical trials the unfavourable profile of AKR is attributed to their non-selectivity and adverse side effects. AKR1A1 selective towards AKR1B1 with safe pharmacophore are highly desirable to suppress polyol pathway and hence reduce chronic diabetic complications. In our current study, we designed to isolate some new natural products from the above mentioned plant (basil) and characterized them with different spectral techniques such as 1H, 13C NMR and 2D NMR spectra, IR and mass spectrometry. The natural product (1) contains coumarin and glucose scaffolds while compounds (2) structure is simply a functionalized benzene ring. A range of coumarin based compound of plant original has been reported as AKR1B1 inhibitors [30]. In our recent study, we have reported coumarin compounds as aldose reductase (AKR1B1) inhibitors [31]. The structure an active molecule has been shown in the Fig. 1a[31]. The isolated compounds were evaluated as anti-diabetic agent via inhibition assay of aldose reductase.
Materials and methods
Conclusion In conclusion, two new natural products 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6′-hydroxyhex-3′-en-1-yl)phenyl propionate (2) has been isolated from Ocimum basilicum. The isolated compounds were evaluated for their inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The compound 1 containing coumarin and glucose scaffold was found to more potent against AKR1B1, an key enzyme of polyol pathway which flux glucose, with IC50 value of 2.095±0.77µM compare to standard sorbinil (IC50=3.14±0.02µM). The natural product 2, although a simple functionalized benzene ring based molecule, yet showed activity (IC50=4.324±1.25µM) slightly less than standard sorbinil and can be modulate via simple chemical modifications. Altogether, the current study provides two molecules which could potential serve as lead for the development of AKR1B1 inhibitor for the cure of diabetic complications.
Acknowledgement
Introduction Scutellaria is a unique cosmopolitan genus of the subfamily Scutellarioideae belonging to Lamiaceae (Labiatae) family. About 360 species are found spread throughout the world and in different climatic areas. Plants of this genus have been widely used in local medicine of many countries of the world for thousands of years (Gousiadou et al., 2007, Melkani et al., 2007). Moreover, modern pharmacology research has confirmed that the extracts or pure, isolated compounds of Scutellaria possess anti-inflammatory, antitumor, hepatoprotective, antioxidant, anticonvulsant, antibacterial and antiviral effects (Min, 2009, Tan et al., 2006, Yin et al., 2004). The metabolites, mainly flavonoids, are claimed to be responsible for the biological activity (Bruno et al., 2002, Shang et al., 2010).