Ioannis Nicolaou

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.

Design and synthesis of novel series of pyrrole based chemotypes and their evaluation as selective aldose reductase inhibitors. A case of bioisosterism between a carboxylic acid moiety and that of a tetrazole.

Pyrrolyl-propionic and butyric-acid derivatives 1 and 2 were synthesized in order to study the effect of the variation of the methylene chain in comparison to the previously reported pyrrolyl-acetic acid compound I, which was found as potent aldose reductase inhibitor, while the pyrrolyl-tetrazole derivatives 3-5 were prepared as a non-classical bioisosteres of a carboxylic acid moiety. Also, pyrrolyl-tetrazole isomers 6 and 7 without an alkyl chain between the two aromatic rings were synthesized. The in vitro aldose reductase inhibitory activity of the prepared 1-7 compounds were estimated and compared with that of the initial compound (I). Overall, the data indicate that the presented chemotypes 6 and 7 are a promising lead compounds for the development of selective aldose reductase inhibitors, aiming to the long-term complications of diabetes mellitus.

Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent

BackgroundTardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D2 and serotonin 5-HT1A receptors in in vitro competition binding assays. In the present work, we tested its p-toluenesulfonyl derivative (TPBIA) for behavioral effects in rats, related to interactions with central dopamine receptors and its antioxidant activity.MethodsAdult male Fischer-344 rats grouped as: i) Untreated rats: TPBIA was administered i.p. in various doses ii) Apomorphine-treated rats: were treated with apomorphine (1 mg kg-1, i.p.) 10 min after the administration of TPBIA. Afterwards the rats were placed individually in the activity cage and their motor behaviour was recorded for the next 30 min The antioxidant potential of TPBIA was investigated in the model of in vitro non enzymatic lipid peroxidation.Resultsi) In non-pretreated rats, TPBIA reduces the activity by 39 and 82% respectively, ii) In apomorphine pretreated rats, TPBIA reverses the hyperactivity and stereotype behaviour induced by apomorphine. Also TPBIA completely inhibits the peroxidation of rat liver microsome preparations at concentrations of 0.5, 0.25 and 0.1 mM.ConclusionTPBIA exerts dopamine antagonistic activity in the central nervous system. In addition, its antioxidant effect is a desirable property, since TD has been partially attributed, to oxidative stress. Further research is needed to test whether TPBIA may be used as an antipsychotic agent.

Toward the Development of Innovative Bifunctional Agents To Induce Differentiation and To Promote Apoptosis in Leukemia: Clinical Candidates and Perspectives

Although the outcome of therapy for leukemia has improved over the years, mainly in younger patients, less than a third of adults with acute myeloid leukemia (AML), for example, are cured by current treatments, a fact stressing the need for new therapeutic approaches. Since leukemias are considered disorders of self-renewal, differentiation, and apoptosis of hematopoietic stem cells (HSCs) and/or their early progenitors, the treatment of leukemia is rapidly changing from conventional chemotherapy toward a more innovative individualized and targeted therapy. The discovery of leukemia stems cells (LSCs) in the late 1990s as a minor fraction within the subpopulation of hematopoietic cells and the compelling research efforts initiated thereafter have clearly shown that many malignancies are maintained via stemlike cells having the capacity for indefinite self-renewal. This LSC hypothesis has established the notion that the emergence of drug resistance and the clinical relapse of leukemias following an initial remission induced by cytotoxic or targeted therapy agents is related to acquired mutations of LSCs. Therefore, eradication of LSCs is considered necessary for the radical treatment of leukemias. As a matter of fact, novel exploitable targets for leukemia therapy emerged including enzymes like tyrosine kinases involved in signal transduction pathways, genes encoding proteins that regulate apoptosis and differentiation of malignant cells, celllineage transcriptional factors, angiogenesis factors, and unique proteins driving the cell cycle machinery. Interestingly, within the group of antileukemia agents exist small molecule drugs like tyrosine kinase inhibitors, proteasome inhibitors, farnesyl transferase inhibitors, hypomethylating agents, histone deacetylase inhibitors, mTOR targeting agents, bcl-2 inhibitors, and inhibitors of cyclin-dependent kinases (Figure 1). This paper is a comprehensive overview of the scientific efforts made to develop novel antileukemia therapeutics by presenting chemical, pharmacological, and pharmacogenomic data obtained during preclinical and clinical assessment of these agents.Furthermore, the designated synthesis of newmedicines inducing differentiation, cell cycle arrest, and/or promoting apoptosis along with multitargeted therapeutics will be also discussed. Such novel agents can be used in combination with other agents modulating different signaling pathways and molecular targets within the leukemia cells to overcome the emergence of drug resistance. This information can then be discussed from a pharmacogenomic view of antileukemia therapeutics. Individual genetic variations recorded in antileukemia drug therapy can be critical for personalized medicine and their clinical exploitation can achieve better pharmacotherapy outcomes.

Nutritional Overview on the Management of Type 2 Diabetes and the Prevention of its Complications

Diabetes mellitus is an increasing world health problem; particularly the prevalence of type 2 diabetes has assumed epidemic dimensions in Western industrialized societies. It is mainly the environmental, dietary and lifestyle behavioral factors that are the control keys in the progress of this disease. Several epidemiological studies have linked over nutrition and lack of physical activity with type 2 diabetes. Indeed, the excessive consumption of energy dense foods as source of carbohydrates and fats along with ineffective medical management has negative impact on controlling blood glucose levels and on insulin response. This usually leads to a hyperglycemic state, which is associated with the development of the devastating secondary complications. Dietary guidelines have always been important for people with diabetes mellitus. Nutrition management aims to improve health quality maintaining blood glucose levels in normal range so as to reduce the risk for diabetes complications. A well-balanced diet that provides the essential macro- and micro-nutrients is always an impaired need for a patient with diabetes. In this article nutrition recommendations will be displayed for the management of diabetes type 2 and the prevention of its complications. Particular emphasis will be given to the important role of micronutrients such as trace elements and vitamins as well as to the potentiality of some dietary agents to inhibit aldose reductase enzyme, implicated in the etiology of diabetes complications.

Structure–activity relations on [1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone. The effect of methoxy substitution on aldose reductase inhibitory activity and selectivity

Based on our previous work, we studied the effect of methoxy-substitution as well as the regioposition of the benzoyl-moiety of 4a [(1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone]. On this basis, compounds 4b-c and 5a-c were synthesized and assayed for aldose and aldehyde reductase inhibitory activity. Furthermore, a 4,6-difluoro-5-hydroxyphenyl pattern (9) was studied, in order to verify the optimum position of the phenol-moiety. Compound 5b emerged as the most potent and selective inhibitor. Moreover, further assays proved 5b as a potent antioxidant and an inhibitor of sorbitol accumulation in isolated rat lenses. Combining the above attributes, 5b could serve as a lead compound targeted at long-term diabetes complications.

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.

Pyrrolylbenzothiazole Derivatives as Aldose Reductase Inhibitors

Activation of the aldose reductase enzyme (AR, ALR2, E.C. 1.1.1.21) of the polyol pathway has suggested that it is implicated in a number of pathological conditions: a) in diabetic patients, for the development of the long term complications of the disease, and b) in non diabetic individuals, for ischemic myocardial injury, for abnormal proliferation of vascular smooth muscle cells (which is an important feature of atherosclerosis, restenosis, and hypertension), and for bipolar and unipolar mood disorders. Furthermore, about 29% of human liver cancers overexpress AR which might contribute to their resistance to chemotherapy. Although a considerable number of compounds have been synthesized and shown to be effective aldose reductase inhibitors (ARIs), the only ARI available as a drug is Ono Pharmaceutical’s epalrestat in Japan. However, as the inhibition of AR is considered to be a quite promising therapeutic target, – 11 the already marketed epalrestat as well as new chemical entities are being investigated in clinical trials. In the present study, based on the above, (3benzothiazol-2-yl-pyrrol-1-yl)acetic acid (6) and 4(benzothiazol-2-yl-2-benzoylpyrrol-1-yl)acetic acid (9) (Scheme 1) were synthesized and tested for AR inhibitory activity. The design of structure 6 was based on the reported AR inhibitory ability of (3benzoylpyrrol-1-yl)acetic acid as well as the putative non-classical bioisosteric relationship between a carbonyl group and the thiazole ring. Compound 9 combines structural features of 6 and of (2benzoylpyrrol-1-yl)acetic acid. The latter is also an ARI although comparatively weaker than its C-3 isomer.

1-Hydroxypyrazole as a bioisostere of the acetic acid moiety in a series of aldose reductase inhibitors.

Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailability (carboxylic acids). In this work, we succeeded in the bioisosteric replacement of an acetic acid moiety with that of 1-hydroxypyrazole. This new scaffold appears to have a superior physicochemical profile, while attaining inhibitory activity in the submicromolar range.

HPLC-based lipophilicity of pyrrolyl-acetic acid ARIs: Relationships with biological activity

Reversed phase HPLC was used to assess the lipophilicity of a series pyrrolyl-acetic acid derivatives with aldose reductase inhibitory activity. The pH conditions were adjusted at 3.0 to investigate the behavior of the neutral species and at pH 7.4, at which the ionized form predominates, using phosphate and MOPS buffer. Retention was monitored in absence and in presence of different amounts of n-octanol in the mobile phase in order to explore the chromatographic conditions which best reproduce the octanol-water partition or distribution coefficients. The effect of n-octanol in retention was systematically studied and its role in lipophilicity assessment was evaluated. Nevertheless rather moderate regression equations were obtained, which deviated significantly from the ideal 1:1 correlation. No significant effect of buffer was observed. The appropriateness of retention factors to be used in correlation with aldose reductase inhibitory activity was further evaluated and compared to the efficiency of the corresponding octanol-water logP values.