Polyxeni Alexiou

Aldose Reductase Enzyme and its Implication to Major Health Problems of the 21st Century

Aldose reductase enzyme (ALR2) of the polyol metabolic pathway, apart from its role as detoxifying enzyme towards toxic aldehydes, osmoregulator in the kidney and regulator of sperm maturation, was first found to be implicated in the etiology of the long term diabetic complications. However, to date, emerging reports have suggested that under normal glucose concentration, ALR2 may be up-regulated by factors other than hyperglycemia and therefore be involved also in other pathological processes that have become major threats to human health in the 21(st) century. Such pathologies are a number of cardiac disorders, inflammation, mood disorders, renal insufficiency and ovarian abnormalities. In addition, ALR2 was found to be over-expressed in different human cancers such as liver, breast, ovarian, cervical and rectal cancers. Although several aldose reductase inhibitors (ARIs) have progressed to the clinical level, only one is currently on the market. Thus, attention is currently targeted to discover ARIs of distinct chemical structures, being neither hydantoin nor carboxylic acid derivatives. The present review focuses on the molecular mechanisms by which ALR2 is implicated in a number of pathologies, on various aspects concerning its catalytic mechanism and its active site, and on the main classes of ARIs that have been developed to date, as well as on reported (quantitive) structure-activity relationships. The presented data aim to support the notion that ARIs are of pharmacotherapeutic interest for the pharmaceutical community and highlight essential aspects for the development of efficient and potent ARIs.

RAGE: A Multi-Ligand Receptor Unveiling Novel Insights in Health and Disease

Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimers disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community. In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.

A Diverse Series of Substituted Benzenesulfonamides as Aldose Reductase Inhibitors with Antioxidant Activity: Design, Synthesis, and in Vitro Activity

We have previously reported the successful replacement of a carboxylic acid functionality with that of a difluorophenolic group on the known aldose reductase inhibitors (ARIs) of 2-(phenylsulfonamido)acetic acid chemotype. In the present work, based on bioisosteric principles, additional 2,6-difluorophenol and tetrazole, methylsulfonylamide, and isoxazolidin-3-one phenylsulfonamide derivatives were synthesized and tested in vitro in protocols primarily related to the long-term diabetic complications. Most of the compounds were found as ARIs at IC(50) < 100 μM, while the introduction of the 4-bromo-2-fluorobenzyl group in a phenylsulfonamidodifluorophenol structure resulted in a compound (4c) presenting a submicromolar inhibitory profile. However, the derivatives of tetrazole, methylsulfonylamine, and the (R)-enantiomer of isoxazolidin-3-one did not exhibit appreciable ARI activity. The selectivity of the active ARIs is also discussed. Furthermore, the synthesized compounds exhibited potent antioxidant potential (homogeneous and heterogeneous systems).

Novel aldose reductase inhibitors: a patent survey (2006--present).

Introduction: Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors. Areas covered: Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest. On the spotlight were patents enhancing the therapeutic usage of aldose reductase inhibitors (ARIs) to various pathological conditions including cancer and inflammation-mediated diseases such as sepsis, asthma, and cancer. Expert opinion: Although new chemical entities are scarcely registered and patented after many years of inconclusive clinical trials, the involvement of ALR2 to inflammatory pathologies might renew the interest in the field of ARIs.

Design and synthesis of N-(3,5-difluoro-4-hydroxyphenyl)benzenesulfonamides as aldose reductase inhibitors.

N-(3,5-Difluoro-4-hydroxyphenyl)benzenesulfonamide (4) and its derivatives 5-7 were prepared as putative bioisosteres of the previously reported aldose reductase inhibitors, which are the N-benzenesulfonylglycine derivatives I-IV. The in vitro aldose reductase inhibitory activity of the prepared compounds is higher than that of the respective glycine derivatives. Furthermore, the parent compound 4 reveals high antioxidant potential. Additionally, the intestine permeability of 4 is determined, and there is initial evidence that there is an operating influx mechanism. Overall, the data indicate that the presented chemotype could serve as a core structure for the design of putative pharmacotherapeutic agents, aiming to the long-term complications of diabetes mellitus.

Antioxidant and aldose reductase inhibitory capacities of Tephrosia humilis aerial parts' extracts

Tephrosia humilis (Leguminosae), is a tropical shrub endemic in central Africa. Species of this genus are used in traditional remedies as antimicrobial, tonic, diuretic, anthelminthic, blood purifier etc [1,2]. Phytochemical analysis of other Tephrosia species resulted in the isolation of coumarins, and several flavonoids [3–9]. The aim of this study was the evaluation of the antioxidant capacity of several plant extracts of Tephrosia humilis (DPPH assay and Co(II)/EDTA -induced luminol chemiluminescence test), as well as their ability to inhibit the aldose reductase enzyme (AR, ALR2, E.C. 1.1.1.21), indicating a potential of this plant to act against the long term diabetic complications [10,11]. After defatting, plant material was extracted in a soxhlet apparatus with methanol and the dry remaining was partitioned with solvents of increasing polarity, giving five different fractions (diethyl ether, ethyl acetate, ethyl acetate residue, n-butanol, water). Antioxidant results according to both tests proved the good antioxidant capacity of the ethyl acetate fraction in comparison to the standards used (trolox and quercetin) [12]. While according to the CL test all other fractions showed low hydroxyl radical scavenging ability, DPPH test results proved that the n-butanolic and ethyl acetate residue fractions are also effective radical scavengers. As about the ALR2 inhibition, all fractions, except the aqueous, were strong inhibitors at the concentration of 25µg/ml in comparison to sorbinil. The n-butanolic and the ethyl acetate fractions inhibited the enzyme above 75%. This research work proves in vitro the good antioxidant capacity of Tephrosia humilis extracts, as well as their strong inhibitory activity against ALR2 enzyme. References: 1. Bashir, A.K. et al. (1992) Fitoterapia 63: 371. 2. Kole, RK et al. (1992)J. Agric. Food Chem. 40: 1208–1210. 3. Ahmad, S. (1986) Phytochem. 25: 955–958. 4. Menichini, F. et al. (1982) Planta Med. 45: 243. 5. Rajani, P. et al. (1988) Phytochem. 27: 648–649. 6. Rao, E.V. et al. (1984) Phytochem. 23: 1493–1501. 7. Venkata, R. et al. (1979) Phytochem. 18: 1581–1582. 8. Hussaini, F.A. et al. (1986) Planta Med. 52: 220–221. 9. Gupta, R.K. et al. (1980) Phytochem. 19: 1264. 10. Nicolaou, I. et al. (2004)J. Med. Chem. 47: 2706–2709. 11. Matthew, J. et al. (2002)J Amer Med Assoc 288: 2579–2582. 12. Termentzi, A. et al. (2006) Food Chem. 98: 599–608