Vol 53, No 2 (2019)

Intranasal administration (INA) of medicines has the advantages of being noninvasive, painless, simple, and convenient. The basic approaches to solving problems with effective delivery of peptides to the brain through nasal membranes are discussed with respect to nasal cavity anatomy and physiology. INA can bypass the blood—brain barrier although proteolysis of the peptides by olfactory epithelium components, i.e., the enzyme barrier, is an obstacle. Pro-Gly-Pro, Pro-Gly-Pro-Leu, Semax, and Selank were used as reference peptides for in vivo experiments. The maximum contents in rat blood plasma of Pro-Gly-Pro-Leu, Semax, Pro-Gly-Pro, and Selank were 0.54, 1.69, 1.30, and 1.04%, respectively, of the administered amount of labeled peptide. The corresponding values in rat brain for Pro-Gly-Pro-Leu, Semax, Pro-Gly-Pro, and Selank reached 0.0013, 0.13, 0.04, and 0.16%. The methionine in Semax was replaced by alanine, glycine, threonine, and tryptophan to minimize its proteolysis during transversal of the enzyme barrier. Liposomes and acetylation of the N-terminal amino acids were also used to improve the stability of Semax. Use of N-acetyl-Semax was shown to be most promising. In vitro experiments used leucine aminopeptidase (incubation medium contained 12.6% Semax after 60 min), dipeptidyl peptidase (95.4%), carboxypeptidases B (96.8%) and Y(51.0%), nasal mucus enzymes (4.0%), and microsomal fractions of rat brain (9.0%) and blood plasma (0.7%). Proteolysis of Semax formed mainly His-Phe-Pro-Gly-Pro, Phe-Pro-Gly-Pro, and Pro-Gly-Pro.

Natural phenolic compounds have inhibition effects on various malignancies. Thymol is one of these compounds present in several plant sources such as ajowan (Trachyspermum ammi) fruits. In this study, thymol was evaluated for its potential cytotoxic activity as well as its effect on apoptotic gene expression in breast cancer cell line. We used the GC-MS technique to identify the essential oil constituents of ajowan. MCF-7 cells were treated by various concentrations of thymol and half maximum inhibitory concentration (IC₅₀) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, morphological alterations and changes of P21, P53 and Mcl-1 gene expression in MCF-7 cells were investigated by microscopic examination and real-time RT-PCR assay. Data from MTT assay indicated that the IC₅₀ values of thymol on MCF-7 cells for 48 h and 72 h were 54 and 62 μg/mL, respectively. Furthermore, this compound significantly affected gene expressions of P53 and P21, but not Mcl-1. Thymol can induce the apoptosis process in MCF-7, and hence it can be considered an anticancer agent in the future.

The synthesis and anticonvulsant activity of new coumarin derivatives are reported. N-(3-Nitrocoumarin-4-yl)-4-aminobutyric acid (1a) at doses of 60 and 80 mg/kg (in the MES test) and methyl N-(3,6-dinitrocoumarin-4-yl)-4-aminobutyrate (1e) at doses of 20 and 40 mg/kg (in the corazole antagonism test) possessed the greatest anticonvulsant activity of the synthesized compounds. The results indicated that the coumarin derivatives were promising for further development as potential anticonvulsant agents.

New antidiabetic agents are being sought because of the global problem with diabetes. Amidoxime derivatives are known to have antidiabetic activity. β-Aminopropionamidoxime bases and pharmacologically acceptable salts of O-aroyl-β-(morpholin-1-yl)propionamidoximes and 5-substituted phenyl-3-β-(piperidin-1-yl and morpholin-1-yl)ethyl-1,2,4-oxadiazoles were screened in vitro for antidiabetic activity manifested as inhibition of α-amylase and α-glucosidase. Compounds with pronounced antidiabetic properties were identified. The series of 3,5-disubstituted 1,2,4-oxadiazoles were more active than the series of O-aroyl-β-aminopropionamidoximes. The results could be used for further in vivo screening of the antidiabetic properties of the most promising compounds with a preliminary assessment of their mean toxic doses in animals.

Two series of new aromatic thiosemicarbazone derivatives were synthesized by condensation of N-(4-cyanophenyl)hydrazine carbothioamide (I) and N-(4-methylsulfanylphenyl)hydrazine carbothioamide (II) with appropriate aromatic aldehydes in order to investigate their antiviral and cytostatic potency. The chemical structures of all compounds were fully characterized by elemental analysis and spectroscopic techniques. The results of the bioassays indicated that compounds Id, Ie, If and IIf proved inhibitory against influenza virus A (EC₅₀ = 13 – 27 μg/mL for strain H1N1 and 9.3 – 18 μg/mL for strain H3N2). Compounds Ig and IIg were the most cytostatic compounds with inhibition of HeLa cell proliferation at an IC₅₀ = 0.3 μg/mL for Ig and 1.9 μg/mL for IIg. Especially, compound Ig showed the highest cytostatic activity with IC₅₀ of 0.30, 0.70 and 2.50 μg/mL against HeLa, CEM and L1210 cell lines, respectively. This inhibition range was within the same order of magnitude as that for cisplatin. Furthermore, molecular modeling was carried out to examine the cytostatic activity and determine the best pharmacophore model as a guide for the design and development of potential prodrugs in future studies.

Angiogenesis plays a critical role in cancer progression and, hence, inhibiting angiogenesis is considered as a key strategy in cancer therapy. In this study, we screened the antiangiogenic and cytotoxic properties of Nyctanthes arbor-tristis Linn. plant of family Oleaceae, which is used in traditional medicine for the treatment of cancer, arthritis and inflammation. The antiangiogenic activity of ethanolic extract of Nyctanthes arbor-trsitis (ENA) was assessed using Chick Chorioallantoic Membrane (CAM) assay. The mechanism of antiangiogenic action was evaluated via gelatin digestion assay for matrix metalloproteinase (MMP) inhibitory activity. Cytotoxic activity of the extract on glioma cells was assessed using MTT and trypan blue dye exclusion assays. ENA impaired capillary formations in chick CAM model and inhibited MMPactivity on gelatin gels in a concentration dependent manner. The extract was found to be cytotoxic on glioma cells at higher concentrations. Bioactivity guided purification of ENA using column chromatography and thin layer chromatography afforded lupeol as the active principle. Lupeol exhibits significant MMPinhibitory activity at a concentration of 2 μg/mL and cytotoxic activity on glioma with an IC₅₀ value of 10.75 μg/mL. The results of this study hold promise for developing this plant as a source of lupeol, a highly bioactive compound against angiogenesis.

5-Chloro-5-fluoro-6-alkoxypyrimidines were synthesized via Cl₂ chlorination of 5-fluorouracil and 1,3-dimethyl-5-fluorouracil in various alcohols and were screened for antiviral activity. High antiviral activity was found for 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil against RS virus and human flu viruses A/H3N2 and A/H1N1pdm09.

A quantitative procedure was developed for determining total flavonoids in horse chestnut buds (Aesculus hippocastanum L.) using differential spectrophotometry at 422 nm and recalculation as rhamnocitrin or 7-O-methylkaempferol (3,5,4′-trihydroxy-7-methoxyflavone), the dominant flavonoid in this raw material. The error of a single determination of total flavonoids in horse chestnut buds with 95% confidence probability was ± 2.23%. The contents of total flavonoids in horse chestnut buds varied from (1.24 ± 0.01) to (2.31 ± 0.03)%.

The properties of gels prepared from collagen and the natural polyphenol taxifolin were studied. The degradation rate of the gel was shown to decrease with increasing fraction of functionalized taxifolin in it. Gel including polyphenol exhibited iron(II)-binding and iron(III)-reducing activity whereas polyphenol released from the gel could reduce iron ions but did not exhibit significant iron-binding activity. Oxidative modification of the gel increased the polyphenol release rate and decreased its metal-binding properties. In general, the results suggested that stable gels could be produced from collagen and taxifolin and could exhibit antioxidant activity by binding iron ions.

A quantitative UV-spectrophotometric method for determining ribavirin was proposed. The method was demonstrated to be suitable in validation tests. Spectrophotometric determination of ribavirin in tablets was demonstrated to be possible.

There is an error in the order of the author names.

The correct order should be: Muhammad Azhar Abbas,¹ Afeefa Aslam,² Mudassir Iqbal,^3,* Sajid Bashir,³ Tahir Mehmood,⁴ and Joerg Kressler⁵