Medicinal Chemistry

A series of novel ruthenium(II) complexes with electron-donor or electron-acceptor groups in intercalative ligands, [Ru(phen)2(o-MOPIP)]2+(1), [Ru(phen)2(o-MPIP)]2+(2), [Ru(phen)2(o-CPIP)]2+(3) and [Ru(phen)2(o-NPIP)]2+(4) have been synthesized and characterized with elementary, ES-MS, 1H NMR, electronic absorption and emission spectra. The binding properties of these complexes to CT-DNA have been investigated by spectroscopy and viscosity experiments. It’s illustrated that these complexes bind to DNA in a non-classical intercalation mode and their intrinsic binding constants (Kb) for 1, 2, 3 and 4 are calculated as 1.1, 0.35, 0.53 and 1.7 × 105 M-1, respectively. The Quantitative Structure-Activity Relationships (QSAR) of these ruthenium complexes, as well as some other ruthenium complexes congers has been investigated, and a linearity equation have been obtained: logKb=0.2429π+0.0429π2+0.2907σ+0.6 389I+4.3491 (n=12; R=0.9338; F=11.9134; p=0.0030). This results show that the electron-acceptor group and a large hydrophobic group will enhance the DNA binding affinity of ruthenium complexes.

Background: Ziziphus spina-christi is a tropical evergreen tree of Sudanese origin. The plant is commonly used in ethno-medicine for the treatment of many diseases such as malaria, digestive disorders, weakness, hepatic diseases, obesity, urinary problems, diabetes, skin infections, fever, diarrhea and insomnia. However, the pharmaceutical properties and bioactive compounds present in Z. spina-christi are still unknown. Therefore, the aim of the study was to significantly improve and deepen our knowledge about the phenolic composition of Z. spina-christi leaf extracts as well as their antibacterial and potential cytotoxic effects.

Methods: The phytochemical profile of the known compounds in the methanol/water (7:3 v/v) extract of Z. spinachristi leaves were tentatively assigned on the basis of reported analytical data from three to four pieces of independent methods including retention time (tR), UV/Vis spectroscopy, high resolution mass spectrometry (HR-MS) and tandem mass spectrometry (MSn). Four bioactive compounds were purified via preparative-HPLC and identified by means of HPLC-ESI-TOF, HPLC-ESI-MSn, 1H-NMR, 13C-NMR, literature data and authentic reference standards. Antibacterial activities of aqueous and methanol leaf extracts were carried out with six bacterial strains (Bacillus subtilis, Bacillus aquimaris, Clavibacter michiganensis, Escherichia coli, Erwinia amylovora, and Pseudomonas syringae) using an agar diffusion assay. Cytotoxic effects towards the human epidermal keratinocyte cell line HaCaT and rat intestine epithelial IEC-6 cells was assess by cytoskeletal and plasma membrane integrity or analyses of mitochondrial and proliferative activities.

Results: We tentatively assigned fifty-seven phenolic compounds (fifty-two of them are known) to their regioisomeric level in the methanol/water extract of Z. spina-christi leaves. To our knowledge 45 of them were not reported previously in Z. spina-christi and five for the first time in nature. Highly glycosylated flavonoids, proanthocyanidins, and chlorogenic acids were identified as the major components. Preparative-HPLC let to the isolation of four known phytochemicals including quercetin 3-O-(6-O-rhamnosyl-glucoside) (rutin) 26, quercetin 3-O-(2-O-rhamnosyl-arabinoside) 27, phloretin 3',5' di-C-glucoside 39 and quercetin 3-O-(2,6-di-O-rhamnosyl-glucoside) 50. Regarding the antimicrobial assays, the methanol extracts of the plant were found to show higher activity than the aqueous extracts indicating hydrophobic substances of Ziziphus leaves exerting antibacterial activity. The extracts revealed no cytotoxic effects towards the HaCaT or IEC-6 cells.

Conclusions: Several previously known and unknown compounds were indentified in Z. spina-christi leaf extracts. The plant possesses strong antimicrobial activity and no toxicity. Our results therefore suggest that Z. spina-christi extracts might be potentially suitable for topical applications and support the use of the plant in traditional medicine to treat infectious diseases.

A straightforward method has been developed for the synthesis of new anti-inflammatory 1,7-dihydropyrazolo[3,4-d]imidazo[1,2-f]pyrimidine 5 from aminocyanopyrazole. These compounds were screened for their anti-inflammatory, gastroprotective, analgesic, antioxidant and anticandidal activities. Studies of structure-activity relationships have led to selection of compound 6-(4-methoxyphenyl)-3-methyl-1,7-dihydropyrazolo[3,4-d]imidazo[1,2-f]pyrimidine, 5a which exhibited the most potent activities. The structures of all new compounds were elucidated using IR, 1H NMR, 13C NMR and HRMS.

As an important member of CYP1 sub-family, CYP1A2 mediates the metabolisms of approximately 5-10% of the currently clinical medicines, and plays a predominant role in the activation of precarcinogens. F186L mutation in this CYP enzyme is found to have ability to reduce the enzymatic activity. As this mutation is far away from the active site and has no influence on the protein expression, the detailed mechanism for F186L-induced the decrease of the enzymatic activity of CYP1A2 is still unknown. In the current study, we employed molecular dynamics simulation and free energy calculation to study the wild-type and F186L mutant CYP1A2 with a α-naphthoflavone (ANF) bound in the active site. Our simulations showed that instead of changing the backbone structure, the F186L mutation has significant impact on the side-chain conformations, resulting in a smaller active site and larger solvent accessible surface. The former could weaken the binding affinity of ANF in the active site, making the substrate far away from the active site so as to reduce the enzymatic activity. The latter could keep the substrate access channel in a closed state in most case, which was not propitious for the substrate entering into the active site by the substrate access channel. Our findings can reveal an in-depth understanding for the mechanism of the mutation-induced decrease of the enzymatic activity of human CYP1A2, providing useful information on the structure-function relationships of human CYP enzymes.

Prion protein (PrP) has two regions: unstructured region PrP(1-120) and structured region PrP(119-231). In the structured region, there are many segments which have the property of amyloid fibril formation. By theoretical calculations, PrP(126-133), PrP(137-143), PrP(170-175), PrP(177-182), PrP(211-216) have the amyloid fibril forming property. PrP(142-166) has a X-ray crystallography experimental β-hairpin structure, instead of a pure cross-β amyloid fibril structure; thus we cannot clearly find it by our theoretical calculations. However, we can predict that there must be a laboratory X-ray crystal structure in PrP(184-192) segment that will be produced in the near future. The experiments of X-ray crystallography laboratories are agreeing with our theoretical calculations. This article summarized mathematical formulas of prion amyloid fibril cross-β structures of all the above PrP segments currently listed in the Protein Data Bank.

Biomolecular recognition via protein-protein interactions (PPI) is central to the signaling events in most physiological and pathological processes. Hence PPI are considered excellent targets for drug development. In recent years there is considerable interest in the design and development of peptide based drugs as antagonists or agonists of PPI. High potency, great selectivity and better safety profile are significant advantages of peptide therapeutics. The following is a brief review of the rationale and modifications in the design of peptide mimetics of PPI interface.

Background: Diabetes mellitus is a growing epidemic and is the most common cause of chronic kidney disease (CKD) and kidney failure. Diabetic nephropathy affects approximately 20–40% of individuals who have diabetes. Diabetic nephropathy can be detected by the measurement of urine albumin or serum creatinine. Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) was identified in the visceral adipose tissue of OLETF (Otsuka Long-Evans Tokushim a Fatty) rats, an animal model of obesity and type 2 diabetes mellitus (T2DM).

Material and methods: In this study conducted on 70 individuals in the age group of 35-70 years, from Kirkuk General Hospital. study group consists 40 individuals with diabetic nephropathy and 30 ages and sex matched healthy individuals (control).

Reasults: Serum vaspin of diabetic nephropathy patients showed a high significant relationship (p<0.0001). as compared with the controls. There is high significant decrease (p<0.001) in the serum levels of T4 and T3. There is high significant increase (p<0.001) in the serum levels of TSH as compared with the controls. There is high significant increase (p<0.001) in the serum concentration of K+ and uric acid and glucose as compared with the controls. There is high significant decrease (p<0.001) in the serum levels of Ca++ and Na+ as compared with the controls. There is high significant increase (p<0.001) in the serum levels of Cholesterol, TG, LDL and VLDL as compared with the controls. There is significant decrease (p<0.05) in the serum levels of HDL as compared with the controls.

Conclusion: The hormones (vaspin, TSH, T4, T3) have higher diagnostic validity values in the current study, which may be useful as a diagnostic tool to identify recurrence of the diabetic nephropathy syndromes.

Nowadays, many organic contaminants, some of them byproducts from other types of reactions such as dyes or phenolic compounds, or even endocrine disruptors, pharmaceuticals, and personal care products, have been detected in wastewater. Most of them are not controlled and, possibly, can cause harmful effects in aquatic life at environmentally significant concentrations. It is noteworthy, that conventional wastewater treatment plants are not always effective for the removal of these classes of pollutants and so further water treatments are necessary. Therefore, many processes have been investigated for advanced treatment of these effluents as well as for organic pollutants degradation; among these, adsorption process has been used to remove them from wastewater. In addition, there has been a considerable development of new materials with interesting properties, both at large scale and at micro- or nanoscale. Some of these materials are more efficient than others, due to their dimensions in these latter scales, in different kind of applications; specifically, in the field of water treatment. This review is a brief survey of the main characteristics, structures, advantages and recent advances on polymer-clay composites (PCC’s) and polymer-clay nanocomposites (PCN’s), for environmental applications. In the first part are included some basic concepts: composite materials have components with contrasting yet complementary properties; e.g., organoclays which serve as reinforcement of polymeric matrices and give them a larger contact surface and greater mechanical strength. In particular, PCN’s are materials that are used in different applications, for instance to model the morphology of partially crystalline polymers, to remove pollutants from water effluents, to employ them in adsorption processes from water streams, etc. Finally, in the second part, some of developments in the synthesis and applications of these novel materials are discussed; in particular, applications on the field of water pollutants removal through the adsorption process.

Gastrodin (GAS), the main bioactive component of G. elata Blume, has important pharmaceutical and functional activities. The aim of this study is to produce GAS from p-2-hydroxybenzyl alcohol (HBA) through biotransformation. The conversion of exogenous HBA into GAS compound was conducted using cell suspension cultures of Armillaria luteo-virens Sacc. The bioconversion conditions were fully optimized with response surface methodology (RSM), turning out that the optimal transformation conditions composed of 3 mg/mL HBA, 6.5 g/30 mL inoculums level, 1.5% Tween 80, pH 4.5, and transformation temperature at 23°C. Under the optimized conditions, the conversion productivity of GAS reached the highest value (5.65 ± 0.45 mg/L). Verified experiments further validated that the optimized conditions were suitable for predicting the actual process of HBA transformation in the resting-cell system. The bioconversion kinetics model was as well simulated with Michaelis–Menten equation, which showing the suitability. The present study proposed the biotransformation pathway of HBA into GAS by resting cells transformation, indicating that the biotransformation process involved glucosylation reaction. Furthermore, Imprinting Control Region (ICR) mice in vivo demonstrated that the identified gastrodin possessed a significant anti-inflammatory activity. The fundamental data in the present work provides an efficient way to produce GAS through the whole-cells biocatalysis.