Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery.

EF24, a synthetic monocarbonyl analog of curcumin, shows significant potential as an anticancer agent with both chemopreventive and chemotherapeutic properties. It exhibits rapid absorption, extensive tissue distribution, and efficient metabolism, ensuring optimal bioavailability and sustained exposure of the target tissues. The ability of EF24 to penetrate biological barriers and accumulate at tumor sites makes it advantageous for effective cancer treatment. Studies have demonstrated EF24's remarkable efficacy against various cancers, including breast, lung, prostate, colon, and pancreatic cancer. The unique mechanism of action of EF24 involves modulation of the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, disrupting cancer-promoting inflammation and oxidative stress. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through inhibiting the NF-κB pathway and by regulating key genes by modulating microRNA (miRNA) expression or the proteasomal pathway. In summary, EF24 is a promising anticancer compound with a unique mechanism of action that makes it effective against various cancers. Its ability to enhance the effects of conventional therapies, coupled with improvements in drug delivery systems, could make it a valuable asset in cancer treatment. However, addressing its solubility and stability challenges will be crucial for its successful clinical application.

Efficacy of the monocarbonyl curcumin analog C66 in the reduction of diabetes-associated cardiovascular and kidney complications.

Curcumin is a polyphenolic compound derived from turmeric that has potential beneficial properties for cardiovascular and renal diseases and is relatively safe and inexpensive. However, the application of curcumin is rather problematic due to its chemical instability and low bioavailability. The experimental results showed improved chemical stability and potent pharmacokinetics of one of its analogs - (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66). There are several advantages of C66, like its synthetic accessibility, structural simplicity, improved chemical stability (in vitro and in vivo), presence of two reactive electrophilic centers, and good electron-accepting capacity. Considering these characteristics, we reviewed the literature on the application of C66 in resolving diabetes-associated cardiovascular and renal complications in animal models. We also summarized the mechanisms by which C66 is preventing the release of pro-oxidative and pro-inflammatory molecules in the priming and in activation stage of cardiomyopathy, renal fibrosis, and diabetic nephropathy. The cardiovascular protective effect of C66 against diabetes-induced oxidative damage is Nrf2 mediated but mainly dependent on JNK2. In general, C66 causes inhibition of JNK2, which reduces cardiac inflammation, fibrosis, oxidative stress, and apoptosis in the settings of diabetic cardiomyopathy. C66 exerts a powerful antifibrotic effect by reducing inflammation-related factors (MCP-1, NF-κB, TNF-α, IL-1ß, COX-2, and CAV-1) and inducing the expression of anti-inflammatory factors (HO-1 and NEDD4), as well as targeting TGF-ß/SMADs, MAPK/ERK, and PPAR-γ pathways in animal models of diabetic nephropathy. Based on the available evidence, C66 is becoming a promising drug candidate for improving cardiovascular and renal health.

Assessment of Distribution and Diversity of Pyrrolizidine Alkaloids in the Most Prevalent Boraginaceae Species in Macedonia.

Systematic study of extraction efficiency of pyrrolizidine alkaloids (PAs) and corresponding pyrrolizidine alkaloid N-oxides (PANOs) from plant material for subsequent LC/MS analysis was carried out. The optimal extraction was achieved with methanol and one clean up step using SPE C18 column. With the optimized LC-ESI-MS/MS method using ion trap, the distribution and diversity of PAs and PANOs in plant material (leaves, flowers and stems) obtained from wild-growing E. vulgare, E. italicum, S. officinale L., C. creticum and O. heterophylla species from Macedonia was assessed. These widespread Boraginaceae species contain various PAs and PANOs and 25 of them were identified. Based on these qualitative and quantitative analyses, the profiles of 1,2-unsaturated PAs for each sample were obtained and their toxic potential was estimated. The toxic potential of O. heterophylla and C. creticum were assumed to be highest (containing up to 4753 mg/kg and 3507 mg/kg), followed by E. vulgare (up to 1340 mg/kg), S. officinale L. (up to 479 mg/kg) and E. italicum (up to 16 mg/kg). This method can be used for monitoring the inclusion of these secondary metabolites in the food chain in order to contribute in their risk management.

Curcumin analogs (B2BrBC and C66) supplementation attenuates airway hyperreactivity and promote airway relaxation in neonatal rats exposed to hyperoxia.

BACKGROUND: This study was undertaken to test the hypothesis that the newly synthesized curcuminoids B2BrBC and C66 supplementation will overcome hyperoxia-induced tracheal hyperreactivity and impairment of relaxation of tracheal smooth muscle (TSM). MATERIALS AND METHODS: Rat pups (P5) were exposed to hyperoxia (>95% O2 ) or normoxia for 7 days. At P12, tracheal cylinders were used to study in vitro contractile responses induced by methacholine (10-8 -10-4 M) or relaxation induced by electrical field stimulation (5-60 V) in the presence/absence of B2BrBC or C66, or to study the direct relaxant effects elicited by both analogs. RESULTS: Hyperoxia significantly increased contraction and decreased relaxation of TSM compared to normoxia controls. Presence of B2BrBC or C66 normalized both contractile and relaxant responses altered by hyperoxia. Both, curcuminoids directly induced dose-dependent relaxation of preconstricted TSM. Supplementation of hyperoxic animals with B2BrBC or C66, significantly increased catalase activity. Lung TNF-α was significantly increased in hyperoxia-exposed animals. Both curcumin analogs attenuated increases in TNF-α in hyperoxic animals. CONCLUSION: We show that B2BrBC and C66 provide protection against adverse contractility and relaxant effect of hyperoxia on TSM, and whole lung inflammation. Both analogs induced direct relaxation of TSM. Through restoration of catalase activity in hyperoxia, we speculate that analogs are protective against hyperoxia-induced tracheal hyperreactivity by augmenting H2 O2 catabolism. Neonatal hyperoxia induces increased tracheal contractility, attenuates tracheal relaxation, diminishes lung antioxidant capacity, and increases lung inflammation, while monocarbonyl CUR analogs were protective of these adverse effects of hyperoxia. Analogs may be promising new therapies for neonatal hyperoxic airway and lung disease.

In Silico SAR Studies of HIV-1 Inhibitors.

Quantitative Structure Activity Relationships (QSAR or SAR) have helped scientists to establish mathematical relationships between molecular structures and their biological activities. In the present article, SAR studies have been carried out on 89 tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine (TIBO) derivatives using different classifiers, such as support vector machines, artificial neural networks, random forests, and decision trees. The goal is to propose classification models that will be able to classify TIBO compounds into two groups: high and low inhibitors of HIV-1 reverse transcriptase. Each molecular structure was encoded by 10 descriptors. To check the validity of the established models, all of them were subjected to various validation tests: internal validation, Y-randomization, and external validation. The established classification models have been successful. The correct classification rates reached 100% and 90% in the learning and test sets, respectively. Finally, molecular docking analysis was carried out to understand the interactions between reverse transcriptase enzyme and the TIBO compounds studied. Hydrophobic and hydrogen bond interactions led to the identification of active binding sites. The established models could help scientists to predict the inhibition activity of untested compounds or of novel molecules prior to their synthesis. Therefore, they could reduce the trial and error process in the design of human immunodeficiency virus (HIV) inhibitors.

Comparative study of the antioxidant properties of monocarbonyl curcumin analogues C66 and B2BrBC in isoproteranol induced cardiac damage.

AIM: To test the antioxidant properties of the newly synthesized (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC) in parallel with C66 in rats with cardiac hypertrophy. MATERIALS AND METHODS: The protective effects of both C66 and B2BrBC against oxidative stress in rats with cardiac hypertrophy, was studied by evaluating the activity of antioxidant enzymes, the relationship between the ratio of the activities of the antioxidant enzymes R = SOD/(GPx + CAT) and levels of thiols and lipid peroxidation in the heart. In order to gain better understanding of the antioxidant properties of the studied compounds, computational methods were utilized. The properties of selected structurally related derivatives were obtained on optimized geometries for ground states, using semi-empirical PM3 quantum mechanical calculations. KEY FINDINGS: The ratio R shows disequilibrium in rats with induced hypertrophy (p < 0.001). Coextending changes were detected in total and free sulfhydryl group content (p = 0.011 for t-SH and p = 0.008, for free SH, respectively). The results with the B2BrBC, indicated strong thiol prevention reflected in the levels of both t-SH and f-SH. Taking into account the HOMO energies of B2BrBC (-9.398 eV) and C66 (-9.667), it can be concluded that B2BrBC has lower HOMO energy, which makes it a better electron donor and a better antioxidant. SIGNIFICANCE: The obtained results indicated that the antioxidant ability of B2BrBC is positively associated with the catalytic SOD and GPx activities expressed through preserved t-SH levels. It seems plausible that for a compound to exhibit antioxidant activity, as most of the 2,6-bis(benzylidene)cyclohexanones do, they should be good electron donors. IMPACT STATEMENT: Understanding the relationship between cardiac hypertrophy induced oxidative injuries and supporters of endogenous reparatory machinery will help in establishing the beneficial role of adequate antioxidant supplementation. In this study reliable data on the preventive effects of newly synthesized symmetric monocarbonyl curcumin analogue B2BrBC and its role in the prevention of oxidative injuries on three levels (enzymatic, protein and lipid), in the heart hypertrophic onset, were obtained.

Changes in Volatile Compounds during Aging of Sweet Fennel Fruits-Comparison of Hydrodistillation and Static Headspace Sampling Methods.

Two extraction methods for subsequent gas chromatographic (GC) determination of volatiles from freshly harvested and aged fennel fruit samples (Foeniculum vulgare Mill.,ssp. vulgare var. dulce) have been compared. Hydrodistillation followed by GC-FID and GC-MS analysis was used as a standard method for essential oil characterization, while static headspace followed by GC (SHS-GC-FID) was used as a comparative method for determination of volatile components. As the fennel fruit ages, there is a gradual loss of the volatile components as indicated by the lower yield of essential oil and lower content of volatiles, as indicated by the alternative SHS-GC-FID analysis. Slight differences observed for the main components (trans-anethole, estragole, fenchone, and limonene) using the two methods are negligible, indicating that these volatiles did not undergo chemical transformation during the sample preparation procedures. A difference in anisaldehyde content was observed when the composition of the hydrodistilled essential oil was compared with the SHS-GC-FIDanalysis of volatiles and explanation for the variation of anisaldehyde content and the origin of other compounds was suggested. Comparison of the obtained results showed that limonene oxides, carvone and carveolare detectable in SHS-GC-FID analysis of the aged fennel fruits, while in hydrodistilled samples analyzed by GC-FID they were not present. Another observed difference was the appearance of products in significant amounts with higher retention times than trans-anethole, namely threo- and erythro-anethole ß-hydroxymethylether and anethole glycol that are not detectable in the essential oil obtained by hydrodistillation. So, the relative abundance of the major components is comparable between these two methods for fennel seed up to 3 years from harvest and they can be used interchangeably depending on the purpose and amount of material. Furthermore, SHS-GC-FID can be used for assessment of maximum storage time and quality of fennel fruit suitable for human consumption.

Simultaneous Determination of Essential Oil Components and Fatty Acids in Fennel using Gas Chromatography with a Polar Capillary Column.

Cultivated and wild growing samples of fennel (Foeniculum vulgare Mill., Apiaceae) from R. Macedonia were studied for their volatiles and fatty acid composition. The main essential oil components isolated via hydrodistillation were: trans-anethole (>80%), estragole (< 6%), limonene (< 6%), anisaldehyde (< 1%) and 0.5 % fenchone. An alternative method for characterization of both the non-polar volatile and non volatile fractions was developed using n-hexane and dichloromethane (3:1, v/v) in a Soxhlet extraction followed by transesterification. The obtained extracts were then characterized and the dominant fatty acid was 18:1 (petroselinic and oleic acid) 75.0-82.8%, followed by 18:2 (linoleic acid) 10.8-16.2% and other fatty acids: palmitic (4.3-6.9%), stearic (1.2-1.7%) and myristic (0-2.9%). The results for the volatile fraction after Soxhlet extraction and transesterification did not significantly differ from results obtained after hydrodistillation, especially for the main components (trans-anethole, estragole, fenchone and limonene), implying that the developed method can be used for simultaneous determination of volatiles and fatty acids.

Reactions of (benzamidomethyl)triethylammonium chloride with some inorganic nucleophiles in aqueous media.

A variety of benzamidomethyl derivatives were prepared in water under alkaline conditions (pH>9) via reaction of (benzamidomethyl)triethylammonium chloride (1) with different inorganic nucleophiles. Reaction of 1 with hydroxylamine did not give the expected mono(benzamidomethyl)-hydroxylamine (3) but rather gave N,N- di(benzamidomethyl)hydroxylamine (2). Reactions of 1 with sodium azide and potassium cyanide gave benzamidomethyl azide (4a) and benzamidomethyl cyanide (4b) respectively. Potassium thiocyanate and sodium iodide reacted with 1, and the anion- exchanged products (benzamidomethyl)triethylammonium isothiocyanate (5a) and (benzamidomethyl)triethylammonium iodide (5b) were thus obtained. Cyanamide and potassium cyanate reacted readily with 1 and both gave the same mixture of di(benzamidomethyl)amine (7) and tri(benzamidomethyl)amine (8). All the reactions occurred smoothly, under mild conditions, to give the products in moderate to high yields.