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1.  Eliminating the Heart from the Curcumin Molecule: Monocarbonyl Curcumin Mimics (MACs) 
Molecules (Basel, Switzerland)  2014;20(1):249-292.
Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin’s Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin’s assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10–20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer’s disease and malaria.
doi:10.3390/molecules20010249
PMCID: PMC4312668  PMID: 25547726
monocarbonyl analogs of curcumin; MACs; inflammation; cancer; infectious disease; anti-angiogenesis; NF-κB; TNF-α
2.  Multiplexed Analysis of Cage and Cage Free Chicken Egg Fatty Acids Using Stable Isotope Labeling and Mass Spectrometry 
Molecules (Basel, Switzerland)  2013;18(12):14977-14988.
Binary stable isotope labeling couple with LC-ESI-MS has been used as a powerful non-targeted approach for the relative quantification of lipids, amino acids, and many other important metabolite classes. A multiplexed approach using three or more isotopic labeling reagents greatly reduces analytical run-time while maintaining excellent sensitivity and reproducibility. Three isotopic cholamine labeling reagents have been developed to take advantage of the pre-ionized character of cholamine, for ESI, and the ease by which stable isotopes can be incorporated into the cholamine structure. These three cholamine labeling reagents have been used to relatively quantify three fatty acid samples simultaneously. The quantification resulted in the observation of 12 fatty acids that had an average absolute error of 0.9% and an average coefficient of variation of 6.1%. Caged versus cage-free isotope labeling experiments showed that cage-free eggs have an increased level of omega-3 fatty acids as compared to caged eggs. This multiplexed fatty acid analysis provides an inexpensive and expedited tool for broad-based lipid profiling that will further aid discoveries in the mechanisms of fatty acid action in cells.
doi:10.3390/molecules181214977
PMCID: PMC4249618  PMID: 24317525
3.  Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships 
Molecules (Basel, Switzerland)  2013;18(12):14470-14495.
With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990’s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes. However, the details of structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis.
doi:10.3390/molecules181214470
PMCID: PMC4216474  PMID: 24287985
4.  Application Scope and Limitations of TADDOL-Derived Chiral Ammonium Salt Phase-Transfer Catalysts 
Molecules (Basel, Switzerland)  2013;18(4):4357-4372.
We have recently introduced a new class of chiral ammonium salt catalysts derived from easily available TADDOLs. To get a full picture of the scope of application and limitations of our catalysts we tested them in a variety of different important transformations. We found that, although these compounds have recently shown their good potential in the asymmetric α-alkylation of glycine Schiff bases, they clearly failed when we attempted to control more reactive nucleophiles like β-keto esters. On the other hand, when using them to catalyse the addition of glycine Schiff bases to different Michael acceptors it was found necessary to carefully optimize the reaction conditions for every single substrate class, as seemingly small structural changes sometimes required the use of totally different reaction conditions. Under carefully optimized conditions enantiomeric ratios up to 91:9 could be achieved in the addition of glycine Schiff bases to acrylates, whereas acrylamides and methyl vinyl ketone gave slightly lower selectivities (up to e.r. 77:23 in these cases). Thus, together with additional studies towards the syntheses of these catalysts we have now a very detailed understanding about the scope and limitations of the synthesis sequence to access our PTCs and about the application scope of these catalysts in asymmetric transformations.
doi:10.3390/molecules18044357
PMCID: PMC4202194  PMID: 23584056
asymmetric catalysis; tartaric acid; α-alkyation; Michael addition
5.  Macrocyclic Pyridyl Polyoxazoles: Structure-Activity Studies of the Aminoalkyl Side-Chain on G-Quadruplex Stabilization and Cytotoxic Activity 
Molecules (Basel, Switzerland)  2013;18(10):11938-11963.
Pyridyl polyoxazoles are 24-membered macrocyclic lactams comprised of a pyridine, four oxazoles and a phenyl ring. A derivative having a 2-(dimethylamino)ethyl chain attached to the 5-position of the phenyl ring was recently identified as a selective G-quadruplex stabilizer with excellent cytotoxic activity, and good in vivo anticancer activity against a human breast cancer xenograft in mice. Here we detail the synthesis of eight new dimethylamino-substituted pyridyl polyoxazoles in which the point of attachment to the macrocycle, as well as the distance between the amine and the macrocycle are varied. Each compound was evaluated for selective G-quadruplex stabilization and cytotoxic activity. The more active analogs have the amine either directly attached to, or separated from the phenyl ring by two methylene groups. There is a correlation between those macrocycles that are effective ligands for the stabilization of G-quadruplex DNA (ΔTtran 15.5–24.6 °C) and cytotoxicity as observed in the human tumor cell lines, RPMI 8402 (IC50 0.06–0.50 µM) and KB3-1 (IC50 0.03–0.07 µM). These are highly selective G-quadruplex stabilizers, which should prove especially useful for evaluating both in vitro and in vivo mechanism(s) of biological activity associated with G-quaqdruplex ligands.
doi:10.3390/molecules181011938
PMCID: PMC3949622  PMID: 24077174
synthesis; macrocycle; G-quadruplex; G-quadruplex stabilizer; G-quadruplex ligands
6.  Thiosulfoxide (Sulfane) Sulfur: New Chemistry and New Regulatory Roles in Biology 
Molecules (Basel, Switzerland)  2014;19(8):12789-12813.
The understanding of sulfur bonding is undergoing change. Old theories on hypervalency of sulfur and the nature of the chalcogen-chalcogen bond are now questioned. At the same time, there is a rapidly expanding literature on the effects of sulfur in regulating biological systems. The two fields are inter-related because the new understanding of the thiosulfoxide bond helps to explain the newfound roles of sulfur in biology. This review examines the nature of thiosulfoxide (sulfane, S0) sulfur, the history of its regulatory role, its generation in biological systems, and its functions in cells. The functions include synthesis of cofactors (molybdenum cofactor, iron-sulfur clusters), sulfuration of tRNA, modulation of enzyme activities, and regulating the redox environment by several mechanisms (including the enhancement of the reductive capacity of glutathione). A brief review of the analogous form of selenium suggests that the toxicity of selenium may be due to over-reduction caused by the powerful reductive activity of glutathione perselenide.
doi:10.3390/molecules190812789
PMCID: PMC4170951  PMID: 25153879
cystamine; cystathionine γ-lyase (γ-cystathionase); garlic; glutathione persulfide; hydrogen sulfide; mercaptoethanol; perseleno selenium; persulfide; sulfane sulfur; thioglycerol
7.  Click Chemistry in Peptide-Based Drug Design 
Molecules (Basel, Switzerland)  2013;18(8):9797-9817.
Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.
doi:10.3390/molecules18089797
PMCID: PMC4155329  PMID: 23959192
click chemistry; triazoles; application; peptides; drug discovery
8.  Group 11 Metal Compounds with Tripodal Bis(imidazole) Thioether Ligands. Applications as Catalysts in the Oxidation of Alkenes and as Antimicrobial Agents 
Molecules (Basel, Switzerland)  2011;16(8):6701-6720.
New group 11 metal complexes have been prepared using the previously described tripodal bis(imidazole) thioether ligand (N-methyl-4,5-diphenyl-2-imidazolyl)2C(OMe)C(CH3)2S(tert-Bu) ({BITOMe,StBu}, 2). The pincer ligand offers a N2S donor atom set that can be used to coordinate the group 11 metals in different oxidation states [AuI, AuIII, AgI, CuI and CuII]. Thus the new compounds [Au{BITOMe,StBu}Cl][AuCl4]2 (3), [Au{BITOMe,StBu}Cl] (4), [Ag{BITOMe,StBu}X] (X = OSO2CF3 − 5, PF6 − 6) and [Cu{BITOMe,StBu}Cl2] (7) have been synthesized from reaction of 2 with the appropriate metal precursors, and characterized in solution. While attempting characterization in the solid state of 3, single crystals of the neutral dinuclear mixed AuIII-AuI species [Au2{BITOMe,S}Cl3] (8) were obtained and its crystal structure was determined by X-ray diffraction studies. The structure shows a AuIII center coordinated to the pincer ligand through one N and the S atom. The soft AuI center coordinates to the ligand through the same S atom that has lost the tert-butyl group, thus becoming a thiolate ligand. The short distance between the AuI–AuIII atoms (3.383 Å) may indicate a weak metal-metal interaction. Complexes 2–7 and the previously described CuI compound [Cu{BITOMe,StBu}]PF6 (9) have been evaluated in the oxidation of biphenyl ethylene with tert-butyl hydrogen peroxide (TBHP) as the oxidant. Results have shown that the AuI and AgI complexes 4 and 6 (at 10 mol % loading) are the more active catalysts in this oxidative cleavage. The antimicrobial activity of compounds 2–5, 7 and 9 against Gram-positive and Gram-negative bacteria and yeast has also been evaluated. The new gold and silver compounds display moderate to high antibacterial activity, while the copper derivatives are mostly inactive. The gold and silver complexes were also potent against fungi. Their cytotoxic properties have been analyzed in vitro utilizing HeLa human cervical carcinoma cells. The compounds displayed a very low cytotoxicity on this cell line (5 to 10 times lower than cisplatin) and on normal primary cells derived from C57B6 mouse muscle explants, which may make them promising candidates as potential antimicrobial agents and safer catalysts due to low toxicity in human and other mammalian tissues.
doi:10.3390/molecules16086701
PMCID: PMC4142805  PMID: 25134773
tripodal bis(imidazol) thioether pincer ligands; group 11 metals; oxidation alkenes; antimicrobial; non-toxic
9.  Diversity-Oriented Synthesis Based on the DPPP-Catalyzed Mixed Double-Michael Reactions of Electron-Deficient Acetylenes and β-Amino Alcohols 
Molecules (Basel, Switzerland)  2011;16(5):3802-3825.
In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)–catalyzed mixed double-Michael reactions of β-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products are isolated without complicated work-up. To demonstrate the applicability of mixed double-Michael reactions for the preparation of five-membered-ring heterocycles, we prepared 60 distinct oxazolidines from five β-amino alcohols and 12 electron-deficient acetylenes. We synthesized 36 of these 60 oxazolidines in enantiomerically pure form from proteinogenic amino acid–derived β-amino alcohols.
doi:10.3390/molecules16053802
PMCID: PMC4126835  PMID: 21546881
phosphine catalysis; Michael reaction; oxazolidines; β-amino alcohols; acetylenes
10.  The Mathematics of a Successful Deconvolution: A Quantitative Assessment of Mixture-Based Combinatorial Libraries Screened Against Two Formylpeptide Receptors 
Molecules (Basel, Switzerland)  2013;18(6):6408-6424.
In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays.
doi:10.3390/molecules18066408
PMCID: PMC4106117  PMID: 23722730
combinatorial libraries; mixture-based libraries; harmonic mean mixture model; mathematical modeling; formylpeptide receptors
11.  Protein Structure Validation and Identification from Unassigned Residual Dipolar Coupling Data Using 2D-PDPA 
Molecules (Basel, Switzerland)  2013;18(9):10162-10188.
More than 90% of protein structures submitted to the PDB each year are homologous to some previously characterized protein structure. The extensive resources that are required for structural characterization of proteins can be justified for the 10% of the novel structures, but not for the remaining 90%. This report presents the 2D-PDPA method, which utilizes unassigned residual dipolar coupling in order to address the economics of structure determination of routine proteins by reducing the data acquisition and processing time. 2D-PDPA has been demonstrated to successfully identify the correct structure of an array of proteins that range from 46 to 445 residues in size from a library of 619 decoy structures by using unassigned simulated RDC data. When using experimental data, 2D-PDPA successfully identified the correct NMR structures from the same library of decoy structures. In addition, the most homologous X-ray structure was also identified as the second best structural candidate. Finally, success of 2D-PDPA in identifying and evaluating the most appropriate structure from a set of computationally predicted structures in the case of a previously uncharacterized protein Pf2048.1 has been demonstrated. This protein exhibits less than 20% sequence identity to any protein with known structure and therefore presents a compelling and practical application of our proposed work.
doi:10.3390/molecules180910162
PMCID: PMC4090686  PMID: 23973992
PDPA; RDC; unassigned; dipolar, protein; structure; model
12.  Chiral Aminophosphines as Catalysts for Enantioselective Double-Michael Indoline Syntheses 
Molecules (Basel, Switzerland)  2012;17(5):5626-5650.
The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient acetylenes is an efficient process for the synthesis of many nitrogen-containing heterocycles. Because the resulting heterocycles contain at least one stereogenic center, this double-Michael reaction would be even more useful if an asymmetric variant of the reaction were to be developed. Aminophosphines can also facilitate the double-Michael reaction and chiral amines are more readily available in Nature and synthetically; therefore, in this study we prepared several new chiral aminophosphines. When employed in the asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and 3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with moderate asymmetric induction.
doi:10.3390/molecules17055626
PMCID: PMC4091971  PMID: 22580397
double-Michael reaction; chiral aminophosphines; anchimeric assistance; indoline
13.  Synthesis of Quaternary Heterocyclic Salts 
Molecules (Basel, Switzerland)  2013;18(11):14306-14319.
The microwave synthesis of twenty quaternary ammonium salts is described. The syntheses feature comparable yields to conventional synthetic methods reported in the current literature with reduced reaction times and the absence of solvent or minimal solvent.
doi:10.3390/molecules181114306
PMCID: PMC4086059  PMID: 24256924
quaternary ammonium salts; microwave synthesis; heterocycles
14.  Anti-Peroxyl Radical Quality and Antibacterial Properties of Rooibos Infusions and Their Pure Glycosylated Polyphenolic Constituents 
Molecules (Basel, Switzerland)  2013;18(9):11264-11280.
The anti-peroxyl radical quality of two aqueous rooibos infusions and solutions of their most abundant glycosylated polyphenols was evaluated using pyrogallol red and fluorescein-based oxygen radical absorbance ratios. It was observed that the artificial infusions, prepared using only the most abundant polyphenols present in rooibos and at concentrations similar to those found in the natural infusions, showed greater antioxidant quality than the latter infusions, reaching values close to those reported for tea infusions. Additionally, the antimicrobial activity of the natural and artificial infusions was assessed against three species of bacteria: Gram (+) Staphylococcus epidermidis and Staphylococcus aureus and Gram (−) Escherichia coli. When compared to the natural infusions the artificial beverages did not demonstrate any bacterostatic/cidal activity, suggesting that the antibacterial activity of rooibos is related to compounds other than the glycosylated polyphenols employed in our study.
doi:10.3390/molecules180911264
PMCID: PMC4067240  PMID: 24036515
ORAC indices; rooibos infusions; glycosylated polyphenols; bacteria; antioxidant capacity
15.  Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts 
Molecules (Basel, Switzerland)  2013;18(8):8945-8958.
In view of the clear evidence that urokinase type plasminogen activator (uPA) plays an important role in the processes of tumor cell metastasis, aortic aneurysm, and multiple sclerosis, it has become a target of choice for pharmacological intervention. The goal of this study was thus to determine the presence of inhibitors of uPA in plants known traditionally for their anti-tumor properties. Crude methanol extracts were prepared from the leaves of plants (14) collected from the subtropical dry forest (Guanica, Puerto Rico), and tested for the presence of inhibitors of uPA using the fibrin plate assay. The extracts that tested positive (6) were then partitioned with petroleum ether, chloroform, ethyl acetate and n-butanol, in a sequential manner. The resulting fractions were then tested again using the fibrin plate assay. Extracts from leaves of Croton lucidus (C. lucidus) showed the presence of a strong uPA inhibitory activity. Serial dilutions of these C. lucidus partitions were performed to determine the uPA inhibition IC50 values. The chloroform extract showed the lowest IC50 value (3.52 μg/mL) and hence contained the most potent uPA inhibitor. Further investigations revealed that the crude methanol extract and its chloroform and n-butanol partitions did not significantly inhibit closely related proteases such as the tissue type plasminogen activator (tPA) and plasmin, indicating their selectivity for uPA, and hence superior potential for medicinal use with fewer side effects. In a further evaluation of their therapeutic potential for prevention of cancer metastasis, the C. lucidus extracts displayed cytostatic activity against human pancreatic carcinoma (PaCa-2) cells, as determined through an MTS assay. The cytostatic activities recorded for each of the partitions correlated with their relative uPA inhibitory activities. There are no existing reports of uPA inhibitors being present in any of the plants reported in this study.
doi:10.3390/molecules18088945
PMCID: PMC4034058  PMID: 23896619
urokinase type plasminogen activator (uPA); uPA inhibitor; fibrin plate assay; Croton lucidus; metastasis; cytostatic activity
16.  A Modular Approach to Triazole-Containing Chemical Inducers of Dimerisation for Yeast Three-Hybrid Screening 
Molecules (Basel, Switzerland)  2013;18(9):11639-11657.
The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially “off the shelf” synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy.
doi:10.3390/molecules180911639
PMCID: PMC4031444  PMID: 24064457
click chemistry; yeast three-hybrid approach; CIDs
17.  Stimulation of Natural Killer T Cells by Glycolipids 
Molecules (Basel, Switzerland)  2013;18(12):15662-15688.
Natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d protein. The initial discovery of immunostimulatory glycolipids from a marine sponge and the T cells that respond to the compounds has led to extensive research by chemists and immunologists to understand how glycolipids are recognized, possible responses by NKT cells, and the structural features of glycolipids necessary for stimulatory activity. The presence of this cell type in humans and most mammals suggests that it plays critical roles in antigen recognition and the interface between innate and adaptive immunity. Both endogenous and exogenous natural antigens for NKT cells have been identified, and it is likely that glycolipid antigens remain to be discovered. Multiple series of structurally varied glycolipids have been synthesized and tested for stimulatory activity. The structural features of glycolipids necessary for NKT cell stimulation are moderately well understood, and designed compounds have proven to be much more potent antigens than their natural counterparts. Nevertheless, control over NKT cell responses by designed glycolipids has not been optimized, and further research will be required to fully reveal the therapeutic potential of this cell type.
doi:10.3390/molecules181215662
PMCID: PMC4018217  PMID: 24352021
glycolipid; natural killer T cell; cytokine; innate immunity
18.  Synthesis and Biological Evaluation of 2,4-Diaminopyrimidine-Based Antifolate Drugs against Bacillus anthracis 
Molecules (Basel, Switzerland)  2014;19(3):3231-3246.
Due to the innate ability of bacteria to develop resistance to available antibiotics, there is a critical need to develop new agents to treat more resilient strains. As a continuation of our research in this area, we have synthesized a series of racemic 2,4-diaminopyrimidine-based drug candidates, and evaluated them against Bacillus anthracis. The structures are comprised of a 2,4-diaminopyrimidine ring, a 3,4-dimethoxybenzyl ring, and an N-acryloyl-substituted 1,2-dihydrophthalazine ring. Various changes were made at the C1 stereocenter of the dihydrophthalazine moiety in the structure, and the biological activity was assessed by measurement of the MIC and Ki values to identify the most potent drug candidate.
doi:10.3390/molecules19033231
PMCID: PMC4016962  PMID: 24642909
Gram-positive bacteria; Bacillus anthracis; 2,4-diaminopyrimidine; Heck reaction; antibiotic resistance; dihydrofolate reductase (DHFR); antifolates
19.  Lanthanide-Mediated Dephosphorylation Used for Peptide Cleavage during Solid Phase Peptide Synthesis 
Molecules (Basel, Switzerland)  2013;18(4):3894-3905.
Lanthanide(III) ions can accelerate the hydrolysis of phosphomonoesters and phosphodiesters in neutral aqueous solution. In this paper, lanthanide-mediated dephosphorylation has been applied in aqueous media as an orthogonal cleavage condition that can be employed in conventional solid phase peptide synthesis (SPPS). A phosphorylated polymeric support for SPPS was developed using Boc chemistry. The cleavage of resin-bound phosphates was investigated with the addition of Eu(III), Yb(III), acid or base, a mixture of solvents or different temperatures. To demonstrate the utility of this approach for SPPS, a peptide sequence was synthesized on a phosphorylated polymeric support and quantitatively cleaved with lanthanide ions in neutral aqueous media. The protecting groups for side chains were retained during peptide cleavage using lanthanide ions. This new methodology provides a mild orthogonal cleavage condition of phosphoester as a linker during SPPS.
doi:10.3390/molecules18043894
PMCID: PMC3955260  PMID: 23549296
lanthanide; dephosphorylation; peptide synthesis; solid phase
20.  Effect of Sugars on Artemisinin Production in Artemisia annua L.: Transcription and Metabolite Measurements 
Molecules (Basel, Switzerland)  2010;15(4):2302-2318.
The biosynthesis of the valuable sesquiterpene anti-malarial, artemisinin, is known to respond to exogenous sugar concentrations. Here young Artemisia annua L. seedlings (strain YU) were used to measure the transcripts of six key genes in artemisinin biosynthesis in response to growth on sucrose, glucose, or fructose. The measured genes are: from the cytosolic arm of terpene biosynthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), farnesyl disphosphate (FPS); from the plastid arm of terpene biosynthesis, 1-deoxyxylulose-5-phosphate synthase (DXS), 1-deoxyxylulouse 5-phosphate reductoisomerase (DXR); from the dedicated artemisinin pathway amorpha-4,11-diene synthase (ADS), and the P450, CYP71AV1 (CYP). Changes in intracellular concentrations of artemisinin (AN) and its precursors, dihydroartemisinic acid (DHAA), artemisinic acid (AA), and arteannuin B (AB) were also measured in response to these three sugars. FPS, DXS, DXR, ADS and CYP transcript levels increased after growth in glucose, but not fructose. However, the kinetics of these transcripts over 14 days was very different. AN levels were significantly increased in glucose-fed seedlings, while levels in fructose-fed seedlings were inhibited; in both conditions this response was only observed for 2 days after which AN was undetectable until day 14. In contrast to AN, on day 1 AB levels doubled in seedlings grown in fructose compared to those grown in glucose. Results showed that transcript level was often negatively correlated with the observed metabolite concentrations. When seedlings were gown in increasing levels of AN, some evidence of a feedback mechanism emerged, but mainly in the inhibition of AA production. Together these results show the complex interplay of exogenous sugars on the biosynthesis of artemisinin in young A. annua seedlings.
doi:10.3390/molecules15042302
PMCID: PMC3939791  PMID: 20428043
terpene; sugar signal; secondary metabolism
21.  Protostane and Fusidane Triterpenes: A Mini-Review 
Molecules (Basel, Switzerland)  2013;18(4):4054-4080.
Protostane triterpenes belong to a group of tetracyclic triterpene that exhibit unique structural characteristics. Their natural distribution is primarily limited to the genus Alisma of the Alismataceae family, but they have also been occasionally found in other plant genera such as Lobelia, Garcinia, and Leucas. To date, there are 59 known structures of protostane. Many of them have been reported to possess biological properties such as improving lipotropism, hepato-protection, anti-viral activity against hepatitis B and HIV-I virus, anti-cancer activity, as well as reversal of multidrug resistance in cancer cells. On the other hand, fusidanes are fungal products characterized by the 29-nor protostane structures. They possess antibiotic properties against staphylococci, including the methicillin-resistant staphylococcus aureus (MRSA). Fusidic acid is a representative member which has found clinical applications. This review covers plant sources of the protostanes, their structure elucidation, characteristic structural and spectral properties, as well as biological activities. The fungal sources, structural features, structure-activity relationship and biological activities of fusidanes are also covered in this review. Additionally, the biogenesis of these two types of triterpene is discussed and a refined pathway is proposed.
doi:10.3390/molecules18044054
PMCID: PMC3901436  PMID: 23563857
Alisma; alisol; fusidane; protostane; triterpene
22.  Synthesis of Photoresponsive Dual NIR Two-Photon Absorptive [60]Fullerene Triads and Tetrads 
Molecules (Basel, Switzerland)  2013;18(8):10.3390/molecules18089603.
Broadband nonlinear optical (NLO) organic nanostructures exhibiting both ultrafast photoresponse and a large cross-section of two-photon absorption throughout a wide NIR spectrum may make them suitable for use as nonlinear biophotonic materials. We report here the synthesis and characterization of two C60-(antenna)x analogous compounds as branched triad C60(>DPAF-C18)(>CPAF-C2M) and tetrad C60(>DPAF-C18)(>CPAF-C2M)2 nanostructures. These compounds showed approximately equal extinction coefficients of optical absorption over 400–550 nm that corresponds to near-IR two-photon based excitation wavelengths at 780–1,100 nm. Accordingly, they may be utilized as potential precursor candidates to the active-core structures of photosensitizing nanodrugs for 2γ-PDT in the biological optical window of 800–1,050 nm.
doi:10.3390/molecules18089603
PMCID: PMC3830959  PMID: 23941881
C60-(antenna)x nanostructures; ultrafast intramolecular energy-transfer; NIR two-photon absorption; 2γ-photodynamic therapeutic agent; photosensitizer
23.  The Shorter the Better: Reducing Fixed Primer Regions of Oligonucleotide Libraries for Aptamer Selection 
Molecules (Basel, Switzerland)  2009;14(4):10.3390/molecules14041353.
Oligonucleotide aptamers are highly structured DNA or RNA molecules, or modified versions thereof, that can bind to targets with specific affinities comparable to antibodies. They are identified through an in vitro selection process termed SELEX (Systematic Evolution of Ligands by EXponential enrichment) to recognize a wide variety of targets, from small molecules to proteins, and from cultured cells to whole organisms. Aptamers possess a number of desirable properties, such as ease of synthesis, stability, robustness, and lack of immunogenicity. Standard SELEX libraries require two primers, one on each side of a central random domain, to amplify the target-bound sequences via PCR or RT-PCR. However, these primer sequences cause non-specific binding by their nature, and have been reported to lead to large numbers of false-positive binding sequences, or to interfere with binding of sequences within the random regions. This review is focused on methods which have been developed to eliminate fixed primer interference during the SELEX process.
doi:10.3390/molecules14041353
PMCID: PMC3811027  PMID: 19384268
Aptamer; SELEX
24.  BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR 
Molecules (Basel, Switzerland)  2012;17(8):9971-9989.
Stereochemistry is an important determinant of a molecule's biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS) that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF) determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r2 = 0.89, q2 = 0.78). Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS) for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891).
doi:10.3390/molecules17089971
PMCID: PMC3805266  PMID: 22907158
QSAR; CADD; stereochemistry; enantiomer; molecular asymmetry; chirality
25.  Modulation of Xenobiotic Receptors by Steroids 
Molecules (Basel, Switzerland)  2013;18(7):7389-7406.
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in regulating nuclear receptors; in addition to being ligands of steroid receptors, steroids (and their metabolites) also regulate other NRs, such as the pregnane X receptor and constitutive androstane receptor (termed xenobiotic receptors), which participate in steroid metabolism. Xenobiotic receptors have promiscuous ligand-binding properties, and their structurally diverse ligands include steroids and their metabolites. Therefore, steroids, their metabolism and metabolites, xenobiotic receptors, steroid receptors, and the respective signaling pathways they regulate have functional interactions. This review discusses these functional interactions and their implications for activities mediated by steroid receptors and xenobiotic receptors, focusing on steroids that modulate pathways involving the pregnane X receptor and constitutive androstane receptor. The emphasis of the review is on structure-function studies of xenobiotic receptors bound to steroid ligands.
doi:10.3390/molecules18077389
PMCID: PMC3777271  PMID: 23884115
nuclear receptors; pregnane X receptor; constitutive androstane receptor; steroid

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