Table of Contents

Abstract: Catechins, naturally occurring flavonoids derived from wine and green tea, are known to exhibit multiple health benefits. Epigallocatechin gallate (EGCG) is one of the most widely investigated catechins, but its efficacy in cancer therapy is still inconsistent and limited. The poor stability of EGCG has contributed to the disparity in the reported anti-cancer activity and other beneficial properties. Here we report an innovative enzymatic strategy for the oligomerization of catechins (specifically epicatechin) that yields stable, water-soluble oligomerized epicatechins with enhanced and highly specific anti-proliferative activity for human breast cancer cells. This one-pot oxidative oligomerization is carried out in ambient conditions using Horseradish Peroxidase (HRP) as a catalyst yielding water-soluble oligo(epicatechins). The oligomerized epicatechins obtained exhibit excellent growth inhibitory effects against human breast cancer cells with greater specificity towards growth-inhibiting cancer cells as opposed to normal cells, achieving a high therapeutic differential. Our studies indicate that water-soluble oligomeric epicatechins surpass EGCG in stability, selectivity and efficacy at lower doses.

Abstract: Two new triterpene glucosides, β-D-glucopyranosyl 2α,3β,24-trihydroxyolean- 12-en-28-oate and β-D-glucopyranosyl 2α,3β,23,24-tetrahydroxyurs-12-en-28-oate, in addition to nine known compounds belonging to three different triterpene classes (oleanane-, ursane- and lupane-type) have been isolated from the stems of a specimen of Combretum laxum growing in the “Pantanal” of the central-western region of Brazil. Among the known triterpenes, β-D-glucopyranosyl 2α,3β,6β-trihydroxyolean-12-en-28-oate is reported for the first time in the Combretaceae, while bellericoside and asiatic acid are described for the first time in the genus Combretum. The structures of the isolated compounds have been established on the basis of spectral techniques (1D-, 2D-NMR and MS). Their in vitro antifungal activities against standard strains of Candida albicans, C. krusei and Cryptococcus neoformans were also evaluated in this work.

Abstract: In our previous work we described the preparation and characterization of spray dried hydroxyapatite micro granules loaded with 5-fluorouracil (5-FU). These loaded particles are used as a model drug delivery system (DDS). In this study we examined the in vitro response of two cell lines derived from different tissues to 5-FU loaded granules (LG). Both cell lines, either L929 cells of a mouse fibroblast lineage or cells originating from a rat osteosarcoma (ROS 17/2.8) showed a dose dependent decrease in cell proliferation in response to 5-FU-, either dissolved in the culture medium or loaded onto particles. The response of the two cell lines to loaded and nonloaded particles was different. The effect of LG and of a corresponding concentration of free 5-FU was practically the same for the ROS 17/2.8 cells indicating that ROS 17/2.8 cells were not affected by the carrier material. In contrast, L929 cells showed a slight decrease in cell proliferation also in the presence of granules not loaded with 5-FU. This is thought to be attributed to the inhibition of mitogenesis by phosphocitrates, already demonstrated in fibroblasts. In summary, we found that the loaded 5-FU kept its effectivity after the spray drying process and that the response towards the granules varied with cell type. This is the first step towards a tissue specific DDS.

Abstract: The commercially available aromatic polyketones 1a-d were utilized for the synthesis of the multi-arm1,2,3-selenadiazole derivatives 3a-d. The preparation starts with the reaction between compounds 1a-d and p-toluenesulfonyl hydrazide to give the corresponding tosylhydrazones 2a-d. Subsequent reaction with selenium dioxide leads to regiospecific ring closure of the tosylhydrazones to give the target multi-arm 1,2,3-selenadiazole derivatives in high yield. A 1,2,3-selenadiazole derivative 3e containing an epoxide ring was also prepared. The structures of all the synthesized compounds were confirmed on the basis of spectral and analytical data. The compounds were screened in vitro for their antimicrobial activity against various pathogenic bacterial and Candida strains obtained from King Abdullah Hospital in Irbid -Jordan. Compounds 3a, 3c and 3e were found to be highly active against all the selected pathogens. Compound 3e showed an inhibition zone of 13 mm against the highly resistant P. aruginosa.

Abstract: 2-(1-(4-Bromophenyl)-2-thiocyanatoethylidene)malononitrile (3) undergoes azo coupling with diazotized aromatic amines to afford arylhydrazone derivatives, which are readily cyclized to afford the corresponding 3(2H)-pyridazinimine derivatives upon reflux in aqueous NaOH. Under similar condition an o-cyanoarylhydrazone derivative was cyclized into 6H-pyridazino[1,6-a]quinazolin-6-imine, which in turn was easily transformed into 6H-pyridazino[1,6-a]quinazolin-6-one on reflux in ethanolic/HCl. Compound 3 afforded substituted 5-acetylthiophene derivatives upon reflux in AcOH/HCl mixtures.

Abstract: Polyanionic macromolecules are extremely abundant both in the extracellular environment and inside the cell, where they are readily accessible to many proteins for interactions that play a variety of biological roles. Among polyanions, heparin, heparan sulfate proteoglycans (HSPGs) and glycosphingolipids (GSLs) are widely distributed in biological fluids, at the cell membrane and inside the cell, where they are implicated in several physiological and/or pathological processes such as infectious diseases, angiogenesis and tumor growth. At a molecular level, these processes are mainly mediated by microbial proteins, cytokines and receptors that exert their functions by binding to HSPGs and/or GSLs, suggesting the possibility to use polyanionic antagonists as efficient drugs for the treatment of infectious diseases and cancer. Polysulfated (PS) or polysulfonated (PSN) compounds are a heterogeneous group of natural, semi-synthetic or synthetic molecules whose prototypes are heparin and suramin. Different structural features confer to PS/PSN compounds the capacity to bind and inhibit the biological activities of those same heparin-binding proteins implicated in infectious diseases and cancer. In this review we will discuss the state of the art and the possible future development of polyanionic drugs in the treatment of infectious diseases and cancer.

Abstract: Three novel 5-(2-haloethyl)pyrimidine derivatives were synthesized and characterized by ¹H-NMR, ¹³C-NMR, MS, IR spectra and elemental analysis. Iodine and chlorine atoms in the C-5 side chain were introduced by reaction of 5-(2-hydroxyethyl)pyrimidine with hydroiodic acid and phosphoryl chloride, respectively. The structure of the intermediate α-(1-carbamyliminomethylene)-γ-butyrolactone was determined by X-ray crystal structure analysis. The molecule deviates very slightly from planarity. Three N−H···O hydrogen bonds link the molecules into one-dimensional chains of edge-fused rings.

Abstract: A new phloroglucinol diglycoside 1, together with eight known compounds, were isolated from Hypericum japonicum Thunb. The structure of the new compound 1 was determined by spectroscopic methods to be 4,6-dimethyl-5-O-[α-L-rhamnopyranosyl-(1→6)-α-D-glucopyranosyl] multifidol. Different solvent extracts of Hypericum japonicum Thunb. were tested for in vivo antihypoxic activity using mice, with the EtOAc extract showing better activity.

Abstract: In this research, the radical scavenging activity and reducing power of the ethyl acetate fraction and subfractions of Salvia mirzayanii (SM) have been investigated. The plant material was initially extracted with ethanol. The fractionation was carried out using liquid-liquid extraction, then the ethyl acetate fraction, which showed the greatest antioxidant activity, was selected. This fraction was submitted to column chromatography on a Sephadex LH 20 column eluted with pure MeOH to obtain subfractions A-G. No significant differences exist between the IC₅₀ of Salvia mirzayanii ethyl acetate subfraction C (IC₅₀ = 37.9 ± 0.85), F (IC₅₀ = 40.05 ± 1.4) and quercetin (38.84 ± 0.86), (P > 0.05), indicating that the radical scavenging capacity of these two subfractions and quercetin (antioxidant standard) were similar. The reducing power of the ethyl acetate fraction was less than that of all subfractions, except for subfraction A. The greatest amount of phenolic compounds was found in subfraction E (55.23 ± 4.2) and the lowest in subfraction F (5.23 ± 0.18). The greatest total flavonoid content was established in subfraction D (1.84 ± 0.01) and the lowest was in subfraction A (0.108 ± 0.007).

Abstract: A host-guest assembly, [(C₄₀H₄₄N₂₄O₁₂)·(C₆H₅NO₃)₈·13(H₂O)] (1), based on a partial substituted cucurbituril, α,δ-tetramethylcucurbit[6]uril (TMeQ[6]), and 4-nitrophenol was synthesized and structurally characterized by single-crystal X-ray diffraction. A combination of hydrogen-bonding between the latticed water molecule and the hydroxyl group of 4-nitrophenol, the hydroxyl group of 4-nitrophenol and the carbonyl groups lining the portals in additon, the C-H···π interactions between the 4-nitrophenol molecules could be the driving forces of formation such an exclusion host-guest assembly.

Abstract: Neurodegenerative disorders (NDD) have become the common global health burden over the last several decades. According to World Health Organization (WHO), a staggering 30 million people will be affected by Alzheimer’s disease in Europe and the USA by 2050. Effective therapies in this complex field considering the multitude of symptoms associated with NDD indications, have not been found yet. Based on the results of NDD related studies, prevention appears to be the promise alternative. Antioxidative and anti-inflammatory properties are hypothesized for natural phenolics, a group of plant secondary products that may positively impact neurodegenerative diseases. In these studies, phenolic-rich extracts from less common fruit species: Blue honeysuckle (Lonicera edulis, Turcz. ex. Freyn), Saskatoon berry (Amelanchier alnifolia Nutt.), and Chinese hawthorn (Crateagus pinnatifida Bunge) were obtained and analyzed to detect neuroprotective substances content and establish a potential therapeutic value. High performance liquid chromatography with electrochemical detection was optimized and further applied on analysis of the extracts of less common fruit species. It was observed that Chinese hawthorn and Blue honeysuckle extracts are potent source of neuroprotective phenolic antioxidants. In accordance the results, it appears that the fruit or formulated products may have the potential for the prevention of neurodegenerative diseases.

Abstract: A study of microwave-induced and standard thermal Overman rearrangement of selected allylic trichloroacetimidates 1a-1f, 6-8 to the corresponding acetamides 2a-2f, 9-11 is reported. The microwave-assisted rearrangement of trifluoroacetimidate 13 is also described. Using this methodology, an efficient access to versatile allylic trihaloacetamides building synthons was established.

Abstract: The configurational and conformational behavior of some new 3,3,9,9-tetrasubstituted-2,4,8,10-tetraoxaspiro[5.5]undecane derivatives with axial chirality was investigated by conformational analysis and variable temperature NMR experiments.

Abstract: Color is one of the key characteristics used to evaluate the sensory quality of red wine, and anthocyanins are the main contributors to color. Monomeric anthocyanins and CIELAB color values were investigated by HPLC-MS and spectrophotometry during fermentation of Cabernet Sauvignon red wine, and principal component regression (PCR), a statistical tool, was used to establish a linkage between the detected anthocyanins and wine coloring. The results showed that 14 monomeric anthocyanins could be identified in wine samples, and all of these anthocyanins were negatively correlated with the L*, b* and H*ab values, but positively correlated with a* and C*ab values. On an equal concentration basis for each detected anthocyanin, cyanidin-3-O-glucoside (Cy3-glu) had the most influence on CIELAB color value, while malvidin 3-O-glucoside (Mv3-glu) had the least. The color values of various monomeric anthocyanins were influenced by their structures, substituents on the B-ring, acyl groups on the glucoside and the molecular steric structure. This work develops a statistical method for evaluating correlation between wine color and monomeric anthocyanins, and also provides a basis for elucidating the effect of intramolecular copigmentation on wine coloring.

Abstract: A genuine triterpenoid saponin, platyconic acid A (1) was isolated from the roots extract of Platycodon grandiflorum, together with five known saponins: deapioplatycoside E (2), platycoside E (3), platycodin D₃ (4), platycodin D₂ (5) and platycodin D (6). The structure of 1 was determined on the basis of spectral analysis and chemical evidence.

Abstract: [1,4]Diazepino[2,3-h]quinolone carboxylic acid 3 and its benzo-homolog tetrahydroquino[7,8-b]benzodiazepine-3-carboxylic acid 5 were prepared via PPAcatalyzed thermal lactamization of the respective 8-amino-7-substituted-1,4-dihydroquinoline-3-carboxylic acid derivatives 8, 10. The latter compounds were obtained by reduction of their 8-nitro-7-substituted-1,4-dihydroquinoline-3-carboxylic acid precursors 7, 9 which, in turn, were prepared by reaction of 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4-dihydroquinoline-3-carboxylic acid (6) with each of β-alanine and anthranilic acid. All intermediates and target compounds were characterized using elemental analysis, NMR, IR and MS spectral data. The prepared targets and the intermediates have shown interesting antibacterial activity mainly against Gram positive strains. In particular, compound 8 showed good activity against S. aureus (MIC = 0.39 μg/mL) and B. subtilis (MIC = 0.78 μg/mL). Compounds 5a and 9 have also displayed good antifungal activity against C. albicans (MIC = 1.56 μg/mL and 0.78 μg/mL, respectively). None of the compounds tested showed any anticancer activity against solid breast cancer cell line MCF-7 cells or a human breast adenocarcinoma cell line.

Abstract: Seven parguerane diterpenes: 15-bromo-2,7,19-triacetoxyparguer-9(11)-en-16-ol (1), 15-bromo-2,7,16,19-tetraacetoxyparguer-9(11)-ene (2), 15-bromo-2,19-diacetoxyparguer-9(11)-en-7,16-diol (3), 15-bromo-2,16,19-triacetoxyparguer-9(11)-en-7-ol (4), 15-bromo-2,16-diacetoxyparguer-9(11)-en-7-ol (5), 15-bromoparguer-9(11)-en-16-ol (6), 15-bromoparguer-7-en-16-ol (7), two polyether triterpenes: thyrsiferol (8) and thyrsiferyl 23-acetate (9), and one C₁₅-acetogenin, neolaurallene (10), were isolated from a sample of marine red alga Laurencia saitoi collected off the coast of Yantai. Their structures were established by detailed NMR spectroscopic analysis and comparison with literature data.

Abstract: Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species.

Abstract: A one-pot synthesis of 2-arylbenzothiazoles from the reaction of 2-aminothiophenol and aromatic aldehydes catalysed by cerium (IV) ammonium nitrate (CAN) is reported.

Abstract: Bioassay-guided fractionation of the dichloromethane extract of the leaves of Marila pluricostata led to the isolation of 2α,3β-dihydroxy-D:A-friedoolean-28-oic acid (pluricostatic acid), a new friedelane triterpenoid, (1), ten known triterpenoids and three sterols. Their chemical structures were elucidated through spectroscopic analysis. The less polar fractions, on GC/MS analysis and comparison with a MS library, resulted in the identification of twenty four sesquiterpenoids. The new triterpenoid acid 1 showed cytotoxicity against the MCF-7, H-460, and SF-268 human cancer cell lines with GI₅₀ values from 1.2 to 3.3 μg/mL.