Current Enzyme Inhibition - Volume 10, Issue 1, 2014

Aldose reductase (AR) is an enzyme that catalyzes the rate limiting step of the polyol pathway of glucose metabolism. Besides reducing glucose to sorbitol, it reduces a number of lipid peroxidation derived aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, it also has a pivotal role in inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and ovarian cancer. Furthermore, an excess of AR is found in different human cancers, such as liver, colon, breast, and cervical cancer. AR inhibitors have undergone up to phase-III clinical trials for diabetic complications. They are also reported as safe anti-inflammatory drugs. Therefore, future use of AR inhibitors in down-regulating major multi-diseases and inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns worldwide.

This review article tries to be an update of 2008 Pungitore’s review. Again, this paper tries to summarize the investigation about natural products, synthetic and non-nucleoside compounds with the ability to inhibit enzymes that play a crucial role in DNA metabolism such as replication, transcription, retro-transcription, recombination, and chromosome segregation during mitosis. The focus is placed on DNA polymerases, topoisomerases and reverse transcriptase inhibitors because most of the literature emphasized on their inhibitory activity. A great diversity of chemical compounds encompassing triterpenes, flavonoids, chromones, lipids, iridoids, phytosterols, coumarins, anthracyclines, quinones, protoberberines, tannins, lignans, acetogenins, benzimidazoles and other natural products, produced by different species of organisms, have inhibitory activities against enzymes related to DNA metabolism allowing these enzymes to arise as important molecular targets for cancer and AIDS research.

Various derivatives of a modified estradiol core bearing a fused γ-lactone were designed as non-estrogenic inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The compounds were synthesized, characterized and tested for their ability to inhibit enzyme activity (transformation of estrone into estradiol). The proliferative (estrogenic) activity of the compounds was also investigated on estrogen-sensitive breast cancer T-47D cells. Interestingly, one of the estradiol derivatives (compound 24) showed a dual action by inhibiting 17β-HSD1 (IC50 = 1.0 μM) and by producing an antiestrogenic effect on T-47D cells.

Tramadol is an analgesic drug that binds to specific opioid receptors. It may contribute to the inhibition of neuronal re-uptake of noradrenaline. Catalase is a key enzyme for degrading H2O2 in cells and has various isoforms with different structures and kinetics properties. In this research, the effect of tramadol on the activity of catalase of Pseudomonas and mouse liver was investigated and compared. Tramadol could inhibit Pseudomonas catalase with mixed inhibition while inhibiting mouse liver catalase in a non-competitive manner. The Ki and IC50 values were determined as 0.45 and 1.5 mM for Pseudomonas and 2.8 and 2.5 mM for mouse liver, respectively. SDS-PAGE of partially purified catalases determined different molecular weights for Pseudomonas (Mw 54 kDa) and mouse liver (61 kDa).

The aim of this study consisted in extracting and quantifying phenolic and flavonoids compounds of five selected Algerian plants. The second step was devoted to studying the effects of phenolic compounds on the kinetics catalyzed by two enzymes belonging to the class of hydrolase (the α - amylase and the α - glucosidase) responsible for the digestion of sugars. Finally, we assessed the potential antiradical of our extracts. The results indicate that the phenolic extracts from these plants have inhibitory effects on both enzymes, with Ki values in μg/ml range (18.19-72.14 μg / ml) for the α - amylase and (52.26 - 203.90 μg / ml) for α – glucosidase. The antioxidant activity test shows that our phenolic extracts exhibit good antioxidant capacity comparatively to antioxidants taken as reference with IC50 values which vary from 0.044 μg / ml to 0.452 μg / ml. This work contributes to understanding the role of natural polyphenols in the regulation of oxidative stress and normalization of glycemic disorders.

A series of phenyl alkyl ketone derivatives based phosphodiesterase 4 (PDE4) inhibitors was subjected to 2D Quantitative Structure–Activity Relationships (2D QSAR) and Hologram Quantitative Structure–Activity Relationship (HQSAR) studies. The dataset was divided into training and test sets by applying K-means clustering, and 2D QSAR models were established using stepwise linear regression analysis, replacement method and enhanced replacement methods. The models obtained demonstrated high correlation coefficient (R2=0.8374) and low standard deviation (S=0.4442). The robustness of models was confirmed using leave one out cross validation (R2 cv=0.7189), Y scrambling (R2=0.3640), and by test set prediction (R2 pred=0.6867). Topological, steric, electronic and electrotopological descriptors of phenyl alkyl ketone derivatives showed good correlation with the PDE4 inhibitory activity. HQSAR models were established using various fragment sizes, hologram lengths and fragment types. The top HQSAR model was justified by high R2 value of 0.973 and R2 cv value of 0.641. New molecules were designed based on these results and the activity was predicted using the established models.