Carboxymethylated pyridoindole antioxidants as aldose reductase inhibitors: Synthesis, activity, partitioning, and molecular modeling

Starting from the efficient hexahydropyridoindole antioxidant stobadine, a series of carboxymethylated tetrahydro- and hexahydropyridoindole derivatives was synthesized and tested for the inhibition of aldose reductase, an enzyme involved in the etiology of diabetic complications. In vitro inhibiton of rat lens aldose reductase was determined by a conventional method. Kinetic analysis of (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (5b) and (2-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (5c), the most potent compounds in this series with activities in micromolar range, showed uncompetitive inhibition. In addition to the importance of the acidic function, the inhibition efficacy was highly influenced by the steric conformation of the lipophilic aromatic backbone when comparing tetrahydro- and hexahydropyridoindole congeners. Selectivity with respect to the closely related aldehyde reductase was determined by measuring the corresponding inhibitory activities. Antioxidant action of the novel compounds was documented in a DPPH test and in a liposomal membrane model, oxidatively stressed by peroxyl radicals. The presence of a basicity center at the tertiary nitrogen, in addition to the acidic carboxylic function, predisposes these compounds to form double charged zwitterionic species, a characteristic which may remarkably affect their pH-lipophilicity profile. For compounds 5b and 5c, a maximal distribution ratio in a system comprised of 1-octanol/phosphate buffer was recorded near the neutral physiological pH, the region where the isoelectric point lies. Molecular docking simulations into the ALR2 active site performed for the zwitterionic species provided an explanation for the observed structure–activity relationships and the calculated parameters were in agreement with characteristic differences in the stereoelectronic profiles of the tetrahydro- versus hexahydropyridoindoles. ‘Drug-likeness’ of the novel aldose reductase inhibitors was assessed by applying the criteria of Lipinski’s ‘rule of five’.     

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.     

Synthesis and biological evaluation of novel steroid-modified ether phospholipids

Platelet activating factor is one of the most potent inflammatory ether phospholipid mediators known and structurally modified analogues are of considerable interest as potential therapeutic preparations. Inspired by the proposed structure for a novel endogenous hydroxy-PAF analogue isolated recently from gingival crevicular fluid, we designed and prepared two novel steroid-modified ether phospholipids. These two novel compounds exhibit marked chemical and biological similarities to their endogenous prototype and they antagonize it being less active in inducing washed platelet aggregation through PAF receptors.     

Exploiting the anti-inflammatory properties of olive (Olea europaea) in the sustainable production of functional food and neutraceuticals

Olive oil is an important lipid source of the Mediterranean diet which has been associated with lower incidence of cardiovascular diseases whereas olive pomace (OP), a natural by-product of olive oil production, has been found to contain micro constituents with antioxidant, antithrombotic and antiatherogenic activities. The evaluation of OP in order to produce sustainable functional food and neutraceuticals has been the subject of research over the last years. All recent data, focusing on the anti-inflammatory properties of olive oil derived from olive (Olea europaea) and OP along with the potential production of sustainable functional food and neutraceuticals, are presented in this review.     

Synthesis of derivatives of the keto-pyrrolyl-difluorophenol scaffold: Some structural aspects for aldose reductase inhibitory activity and selectivity

Seven novel ARIs (3a–c, 4a–c and 5) were synthesized with the implementation of an optimized and, partially, selective synthetic procedure, via a Friedel–Crafts acylation reaction. The synthesized ARIs have values of IC₅₀^ALR2 ranging from 0.19 μM (in case of compound 3b) to 2.3 μM (in case of compound 4a), while the values of selectivity index towards ALR1 range from 1 (in case of compound 3b) to 238 (in case of compound 3a). Finally, we found out that the presence of an additional (secondary) aromatic area is not a prerequisite feature for ARI activity.     

Interactions between ammonium and pH of the nutrient solution supplied to gerbera (Gerbera jamesonii) grown in pumice

The interactions between the NH₄-N/total-N supply ratio (N _r) and the pH of the nutrient solution delivered to the plants regarding the nutrient availability and its influence on plant growth and yield were investigated in a gerbera crop grown in pumice. Four treatments obtained by combining a low and a high N _r (0.02 and 0.13 on a molar basis, respectively) with two different levels of nutrient solution pH (5.0 and 5.8, respectively) were compared in a long-term glasshouse experiment. The low N _r resulted in significantly higher pH levels in the rhizosphere, as indicated by the values measured in the drainage water. A high nutrient solution pH further increased pH in the root zone at low N _r but had no influence on it at the higher N _r level. The high pH in the root zone restricted significantly the Cu, Mn, and Zn uptake as indicated by both analytical results and visual symptoms, which were typical for Cu- and Mn-deficiencies. Mn-deficiency was induced only when a low N _r was combined with a high nutrient solution pH. The Cu-deficiency symptoms appeared earlier, were more severe and occurred also when the low N _r was combined with a low nutrient solution pH, but to a lesser extent. As a result of these nutrient deficiencies, both the growth and the flower yield were severely restricted when N _r was low. These results indicate that gerbera is prone to Cu- and Mn deficiencies at pH values above 6 in the rhizosphere. The maintenance of root zone pH below this level in soilless culture is most successfully attained by properly adjusting the NH₄-N/total-N supply ratio rather than the pH of the nutrient solution delivered to the plants.     

Screening the elderly in the community: controlled trial of dependency surveillance using a questionnaire administered by volunteers.

OBJECTIVE--To test the benefits of regular surveillance of the elderly at home using an activities of daily living questionnaire administered by volunteers. DESIGN--Randomised controlled study. PATIENTS--539 Subjects aged 75 and over from two general practices. INTERVENTION--All subjects were visited at the beginning and end of the study by volunteers, who completed a scored activity of daily living questionnaire. The study group were revisited at regular intervals. Individuals with an increase in score greater than 5 were referred to their general practitioners. All interactions with social services and health authorities were recorded for both groups. MAIN OUTCOME MEASURES--Mortality, activity of daily living score, total number of days in institutions, geriatric and psychogeriatric service contacts, primary health care team contacts, use of community support services. RESULTS--The study group were admitted to hospital more often than the controls (335 occasions v 252), but the control group spent 33% more days in institutions, mainly in long term admissions to residential accommodation. The number of falls reported in the control group doubled (from 17 before the first interview to 36 before the last) and in the study group remained unchanged (12 before both interviews). The study group received community support services sooner than the control group. There was no difference between the groups in mortality or activity of daily living score. CONCLUSION--Regular visiting of old people at home by non-professional volunteers using a simple activity of daily living questionnaire is a practical way of identifying problems and initiating action for this group.