Volume 83, Issue 9

It was a great honor for the University of Jordan to organize the 11th Eurasia Conference on Chemical Sciences (EuAsC 2 S-11), which was held at the Dead Sea, Jordan from 6 to 10 October 2010. The main objective of the Eurasia Conferences is to give young chemists and graduate students from developing countries the opportunity to meet and interact with eminent scientists from all over the world. The theme of the 11th Eurasia Conference, “ChemistryCares”, underlines the role of chemistry in society and the responsibility of chemists to improve our lives. The scientific program featured 12 plenary lectures, 108 invited lectures, 36 oral presentations, and more than 100 poster presentations. The topics covered the following major themes: Natural Products Chemistry Pharmaceutical Chemistry and Drug Design Bioorganic Chemistry Organic Synthesis Heterocyclic Chemistry Bioinorganic and Inorganic Chemistry Coordination Programming Materials Science and Nanochemistry Renewable Energy and Water Research Physical and Computational Chemistry Analytical Chemistry Electrochemistry Molecular Aspects of Liquids and Solutions Educational Chemistry In addition, there were 4 workshops, 5 panel discussions, and 5 scientific exhibitions. The conference was attended by 630 participants from 59 countries. Many of the participants were young chemists from Jordan and other developing countries who had the opportunity to meet and interact with prominent scientists from around the world, including three Nobel laureates. We are grateful to all who contributed to the success of the conference, especially the speakers and the national and international sponsors. Musa H. Abu Zarga Conference Editor

Natural products have been a rich source of lead identification for drug discovery and development. Over the last two decades, the impetus for natural product-based lead discovery in pharmaceutical industry has declined, resulting in a productivity and innovation crisis. Most of the focus is now on high-throughput screening of synthetic libraries of compounds against defined biological targets; however, discovery of new molecular entities (NMEs) is still declining in this postgenomic era. With the availability of modern purification, characterization, and yield optimization techniques, and with an established intellectual property rights (IPR) regime, it is now possible to circumvent the problems once associated with natural product-based drug discovery. Our work demonstrates that natural products can lead to cost-effective identification of lead molecules against a defined molecular target. During our recent studies, novel classes of urease and α-glucosidase inhibitors were initially obtained from medicinal plants, and based on these novel structural leads, synthetic libraries of structural analogues were synthesized for structure–activity relationship (SAR) studies. These synthetic analogues have shown potent inhibitory activities against the target enzymes, and their mechanisms of action were studied by kinetic, computational, and NMR-based methods.

Pentalongin, the active principle isolated from the roots of the Central East African medicinal plant Pentas longiflora , revealing the basic skeleton of 3,4-dehydropyranonaphthoquinones, was synthesized by ring-closing metathesis of a suitable precursor. Mollugin, together with the (+)- cis -dihydroxylated analogue and the tetracyclic isagarin have been isolated from P. longiflora as well as from other rubiaceous herbs, which are often used in Chinese folk medicine. Synthetic routes of these natural products are presented, as well as the first syntheses of the natural products 3-hydroxy- and 3-methoxymollugin. Although pyranonaphthoquinones represent a large class of natural products, reports of their naturally occurring 2-aza analogues, all of which have been isolated as 2-aza-anthraquinones, are scarce in the literature. Nevertheless, this class of compounds has been found to possess interesting antitumor, antifungal, and antibiotic properties. Therefore, several synthetic routes to new classes of 2-aza-anthraquinones were developed. In vitro testing of the obtained compounds for their activity against Mycobacterium tuberculosis showed promising results.

A fundamental goal in the field of motor proteins is to identify the conformational changes associated with the hydrolysis of the physiological substrate, ATP, and to define how these conformational changes are modulated by binding to the polymer track and translated into biologically useful movement. We have used electron paramagnetic resonance (EPR) spectroscopy to monitor conformational changes at the nucleotide-binding site of myosin- and kinesin-family motors. A novel set of nucleotide-analog EPR spin probes were synthesized and used to localize a spin moiety at the nucleotide site. This allows a reporter group to be placed with high specificity at the ATP binding site. Our results indicate that the nucleotide-binding site of myosin motors opens when the motor binds to its polymer roadway, actin, while that of kinesin closes on binding to microtubules (MTs). However, the transition is not all-or-none. There is instead an equilibrium between open and closed conformations. The different conformational changes in the two motor families can be correlated with differences in their biochemical cycles. Thus, we can now define the relationship between nucleotide-site structure, biochemistry and polymer binding for the two motors.

Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems (TTDDS). In general, a TTDDS consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. This account presents the progress in the molecular approaches to the design and development of novel drug delivery systems for tumor-targeting chemotherapy in our laboratory.

Bioresources offer tremendous potential by having excellent chemical diversity for drug discovery programs and by serving as templates for synthetic drugs. There are well-known examples of clinically important drugs derived from natural sources. The development of pharmaceutical, nutraceutical, agricultural, and industrial products from bioresources can be used to promote incentives for conservation by providing an economic return to innovative use. Of those sources, medicinal plants have a virtually untapped reserve of original drug molecules, which await determination and chemical and biological investigation. Marine organisms have also gained increasing attention from researchers worldwide due to their chemically diverse secondary metabolites with desirable biological activities. There is still a great need for novel compounds with unique mechanisms of action to treat diseases such as cancer, Alzheimer’s, arthritis, and diabetes. Besides, multiresistance development by the parasites to the present drugs also constitutes another problem for the treatment of parasitic diseases as well as tuberculosis. In this article, 209 plant species belonging to 11 plant families were investigated for cholinesterase inhibitory activity by in vitro Ellman method at 10 μg/ml and 1 mg/ml doses. Among them, Salvia, Rosmarinus , and Fumaria species were found to have the most significant cholinesterase inhibitory activity.

The development of a few worldwide routinely used Pt(II) coordination compounds is described from a mechanistic point of view and related to the molecular aspects of Pt-DNA binding. Mechanistic knowledge developed from these studies is applied nowadays for the design and synthesis of new bifunctional and trifunctional compounds, aimed for use as improved anticancer drugs.

A series of tetranuclear grid-type complexes were prepared by the reaction of the asymmetric multidentate ligand HL (HL = 2-[3-(2-hydroxyphenyl)-1 H -pyrazol-5-yl]-6-pyridine carboxylic acid ethylester) with different metal sources. The tetranuclear copper complex, [Cu 4 (L1) 4 (NO 3 ) 4 (H 2 O) 4 ]·Et 2 O·2MeOH ( 1 , HL1 = 2-[3-(2-hydroxyphenyl)-1 H -pyrazol-5-yl]-6-pyridine carboxylic acid methyl ester) consists of four ligands, four copper ions, four nitrate ions and four water molecules, forming a [2 × 2] grid structure, in which all four copper ions have the same coordination environment. On the other hand, the corresponding nickel and cobalt complexes, [M 4 (L2) 4 (H 2 O) 4 ]·4MeOH·6H 2 O (M = Ni ( 2 ) and Co ( 3 ), (H 2 L2 = 6-[1,3-dioxo-3-(2-phenyl)propionyl]pyridine-2-carboxylic acid)), have a similar grid core structure to the copper complex with four metal ions, four ligand molecules, and four water molecules, however, in these clusters there are two kinds of coordination site for the metal ions. Temperature-dependent magnetic susceptibility measurements for all complexes demonstrated that antiferromagnetic interactions between the metal ions were in operation. The magnetic susceptibility data of the copper and nickel complexes were analyzed using a tetranuclear model based on H = –2 J ( S 1 S 2 + S 2 S 3 + S 3 S 4 + S 4 S 1 ) to give best-fit parameters of g = 2.11(1), J = –1.39(3) cm –1 and g = 2.19(1), J = –0.44(2) cm –1 , respectively.

Anion-exchange chromatography resolves human plasma low-density lipoprotein (LDL) into 5 subfractions, with increasing negative surface charge in the direction of L1 to L5. Unlike the harmless L1 to L4, the exclusively atherogenic L5 is rejected by the normal LDL receptor (LDLR) but endocytosed into vascular endothelial cells (ECs) through the lectin-like oxidized LDL receptor-1 (LOX-1). Analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and 2-dimensional electrophoresis showed that the protein framework of L1 was composed mainly of apolipoprotein (apo) B100, with an isoelectric point (pI) of 6.620. There was a progressively increased association of additional proteins, including apoE (pI 5.5), apoAI (pI 5.4), apoCIII (pI 5.1), and apo(a) (pI 5.5), from L1 to L5. Liquid chromatography data-independent parallel-fragmentation mass spectrometry (LC/MS E ) was used to quantify protein distribution in all subfractions. On the basis of weight percentages, L1 contained 99 % apoB-100 and trace amounts of other proteins. In contrast, L5 contained 60 % apoB100 and substantially increased amounts of apo(a), apoE, apoAI, and apoCIII. The compositional characteristics contribute to L5’s electronegativity, rendering it unrecognizable by LDLR. LOX-1, which has a high affinity for negatively charged ligands, is known to mediate the signaling of proinflammatory cytokines. Thus, the chemical composition-oriented receptor selectivity hinders normal metabolism of L5, enhancing its atherogenicity through abnormal receptors, such as LOX-1.

Enzyme inhibitors play a significant role in the drug discovery process. For instance, acetylcholinesterase (AChE) inhibitors have applications in curing Alzheimer’s disease (AD), senile dementia, ataxia, myasthenia gravis, and Parkinson’s disease. Glutathione S -transferase (GST) inhibitors have applications as adjuvants to overcome anticancer and antiparasitic drug resistance problems. Compounds inhibiting the activity of α-glucosidase are used to treat type 2 diabetes mellitus and obesity problems. This article describes the identification of natural products exhibiting AChE, GST, and α-glucosidase inhibitory activities from medicinally important plants. Additionally, structure–activity relationship (SAR) studies of these newly discovered enzyme inhibitors are also discussed.

The molecular mechanisms of carcinogenesis involving heavy metal ions are not yet fully understood. Histones surrounding DNA are believed to be primary targets for metal ion binding, and such interactions may play a direct or indirect role in metal-induced toxicity carcinogenesis. This paper reviews our results of approximately the last 10 years in this area, starting from small peptide fragments and models of various histones and ending with longer ones. It was found that almost all peptide models reacted strongly with metal ions, and in some cases the peptides in the presense of Cu(II) or Ni(II) were hydrolyzed. Oxidation of deoxyguanosine to 8-oxo-deoxyguanosine under physiological pH values was also observed in the presense of mild oxidation agents like H 2 O 2 and certain metal ion–peptide complexes. With longer peptide chain models, a DNA strand breakage analysis was also carried out, indicating an increased DNA damage by Cu 2+ /H 2 O 2 and Ni 2+ /H 2 O 2 reaction mixtures. The results lead to proposals of possible mechanistic pathways of carcinogenesis caused by Cu(II) and Ni(II).

The manuscript focuses on the properties of phthalocyanines (Pcs) that are required for them to be employed as photosensitizers in applications such as photodynamic therapy (PDT). High triplet-state quantum yields and lifetimes as well as high singlet-oxygen quantum yields are required for a good photosensitizer. In addition, absorption of the photosensitizer in the red region of the electromagnetic spectrum is also required, and this can be achieved by ring expansion, substitution with electron-donating ligands, and change of the central metal among others. Quantum dots (QDs) are efficient accumulators of light energy, and they can transfer this energy to molecules that possess a very efficient ability to generate singlet oxygen through a process called Förster resonance energy transfer (FRET). Thus, there is a decrease in the fluorescence quantum yield of the QDs when in the vicinity of Pcs. Triplet quantum yields of the Pcs increase in the presence of QDs.

A five-membered metallacycloallene complex, 1-zirconacyclopenta-2,3-diene, was prepared from low-valent zirconocene and 2,4-bis(trimethylsilyl)but-1-en-3-yne. The complex reacted with carbonyl compounds to afford alkynyl alcohols after hydrolysis via C=O insertion into Zr–C bond. Similarly, nitriles inserted into the Zr–C bond to give the corresponding ketones after hydrolysis. The insertion of C=O and CN selectively took place at zirconium-sp 3 carbon of the metallacycle.

Virgin coconut oil (VCO) is a vegetable oil that is extracted from fresh coconut meat and is processed using only physical and other natural means. VCO was compared to refined, bleached, and deodorized coconut oil (RCO) using standard quality parameters, 31 P nuclear magnetic resonance (NMR) spectroscopy, and headspace solid-phase micro-extraction/gas chromatography mass spectrometry (SPME/GCMS). VCO tends to have higher free fatty acids (FFAs), moisture, and volatile matter and lower peroxide value than RCO. However, the range of values overlap and no single standard parameter alone can be used to differentiate VCO from RCO. Using 31 P NMR, VCO and RCO can be distinguished in terms of the total amount of diglycerides: VCO showed an average content (w/w %) of 1.55, whereas RCO gave an average of 4.10. There was no overlap in the values found for individual VCO and RCO samples. There are four common methods of producing VCO: expeller (EXP), centrifuge (CEN), and fermentation with and without heat. VCO products prepared using these four methods could not be differentiated using standard quality parameters. Sensory analysis showed that VCO produced by fermentation (with and without heat) could be distinguished from those produced using the EXP and CEN methods; this sensory differentiation correlated with the higher levels of acetic acid and octanoic acid in the VCO produced by fermentation. Studies on physicochemical deterioration of VCO showed that VCO is stable to chemical and photochemical oxidation and hydrolysis. VCO is most susceptible to microbial attack, which leads to the formation of various organic acids, in particular, lactic acid. However, at moisture levels below 0.06 %, microbial action is significantly lessened.

Errata: Discovery of the elements with atomic numbers greater than or equal to 113 (IUPAC Technical Report). (Robert C. Barber, Paul J. Karol, Hiromichi Nakahara, Emanuele Vardaci, and Erich W. Vogt). Pure Appl. Chem. 83, 1485–1498 (2011); doi:10.1351/PAC-REP-10-05-01