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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Strategies for Optimizing Water-Exchange Rates of Lanthanide-Based Contrast Agents for Magnetic Resonance Imaging 
Molecules (Basel, Switzerland)  2013;18(8):9352-9381.
This review describes recent advances in strategies for tuning the water-exchange rates of contrast agents for magnetic resonance imaging (MRI). Water-exchange rates play a critical role in determining the efficiency of contrast agents; consequently, optimization of water-exchange rates, among other parameters, is necessary to achieve high efficiencies. This need has resulted in extensive research efforts to modulate water-exchange rates by chemically altering the coordination environments of the metal complexes that function as contrast agents. The focus of this review is coordination-chemistry-based strategies used to tune the water-exchange rates of lanthanide(III)-based contrast agents for MRI. Emphasis will be given to results published in the 21st century, as well as implications of these strategies on the design of contrast agents.
doi:10.3390/molecules18089352
PMCID: PMC3775326  PMID: 23921796
magnetic resonance imaging; contrast agents; PARACEST; water-exchange rate
17.  Spatial Control of DNA Reaction Networks by DNA Sequence 
Molecules (Basel, Switzerland)  2012;17(11):13390-13402.
We have developed a set of DNA circuits that execute during gel electrophoresis to yield immobile, fluorescent features in the gel. The parallel execution of orthogonal circuits led to the simultaneous production of different fluorescent lines at different positions in the gel. The positions of the lines could be rationally manipulated by changing the mobilities of the reactants. The ability to program at the nanoscale so as to produce patterns at the macroscale is a step towards programmable, synthetic chemical systems for generating defined spatiotemporal patterns.
doi:10.3390/molecules171113390
PMCID: PMC3764599  PMID: 23143151
reaction-diffusion; electrophoresis; chemical reaction networks; DNA circuits; strand displacement reactions
18.  Benchmarking Ligand-Based Virtual High-Throughput Screening with the PubChem Database 
Molecules (Basel, Switzerland)  2013;18(1):735-756.
With the rapidly increasing availability of High-Throughput Screening (HTS) data in the public domain, such as the PubChem database, methods for ligand-based computer-aided drug discovery (LB-CADD) have the potential to accelerate and reduce the cost of probe development and drug discovery efforts in academia. We assemble nine data sets from realistic HTS campaigns representing major families of drug target proteins for benchmarking LB-CADD methods. Each data set is public domain through PubChem and carefully collated through confirmation screens validating active compounds. These data sets provide the foundation for benchmarking a new cheminformatics framework BCL::ChemInfo, which is freely available for non-commercial use. Quantitative structure activity relationship (QSAR) models are built using Artificial Neural Networks (ANNs), Support Vector Machines (SVMs), Decision Trees (DTs), and Kohonen networks (KNs). Problem-specific descriptor optimization protocols are assessed including Sequential Feature Forward Selection (SFFS) and various information content measures. Measures of predictive power and confidence are evaluated through cross-validation, and a consensus prediction scheme is tested that combines orthogonal machine learning algorithms into a single predictor. Enrichments ranging from 15 to 101 for a TPR cutoff of 25% are observed.
doi:10.3390/molecules18010735
PMCID: PMC3759399  PMID: 23299552
virtual screening; machine learning; quantitative structure-activity relations (QSAR); high-throughput screening (HTS); cheminformatics; PubChem; BCL
19.  Quinones as Key Intermediates in Natural Products Synthesis. Syntheses of Bioactive Xanthones from Hypericum perforatum 
Molecules (Basel, Switzerland)  2009;14(8):2857-2861.
Two bioactive xanthones from Hypericum perforatum have been synthesized by direct routes. Benzo[c]xanthone 5 can be prepared from intermediate 4.
doi:10.3390/molecules14082857
PMCID: PMC3717578  PMID: 19701129
photoacylation; green chemistry; xanthones
20.  Peptide-Based Selective Inhibitors of Matrix Metalloproteinase-Mediated Activities 
Molecules (Basel, Switzerland)  2012;17(12):14230-14248.
The matrix metalloproteinases (MMPs) exhibit a broad array of activities, some catalytic and some non-catalytic in nature. An overall lack of selectivity has rendered small molecule, active site targeted MMP inhibitors problematic in execution. Inhibitors that favor few or individual members of the MMP family often take advantage of interactions outside the enzyme active site. We presently focus on peptide-based MMP inhibitors and probes that do not incorporate conventional Zn2+ binding groups. In some cases, these inhibitors and probes function by binding only secondary binding sites (exosites), while others bind both exosites and the active site. A myriad of MMP mediated-activities beyond selective catalysis can be inhibited by peptides, particularly cell adhesion, proliferation, motility, and invasion. Selective MMP binding peptides comprise highly customizable, unique imaging agents. Areas of needed improvement for MMP targeting peptides include binding affinity and stability.
doi:10.3390/molecules171214230
PMCID: PMC3678729  PMID: 23201642
matrix metalloproteinase; protease inhibitor; secondary binding site; cyclic peptide; phage display; triple-helix
21.  Insights on Cytochrome P450 Enzymes and Inhibitors Obtained Through QSAR Studies 
Molecules (Basel, Switzerland)  2012;17(8):9283-9305.
The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.
doi:10.3390/molecules17089283
PMCID: PMC3666846  PMID: 22864238
3D-QSAR; SAR; binding/active site; CoMFA; pharmacophore
22.  Synthesis and Characterization of Novel Unsymmetrical and Symmetrical 3-Halo- or 3-Methoxy-substituted 2-Dibenzoylamino-1,4-naphthoquinone Derivatives 
Molecules (Basel, Switzerland)  2013;18(2):1973-1984.
Symmetrical and unsymmetrical 3-halo- or 3-methoxy- substituted 2-dibenzoylamino-1,4-naphthoquinone analogs were synthesized with an average yield of 45% via sodium hydride promoted bis-acylation of 2-amino-3-chloro-1,4-naphthoquinone, 2-amino-3-bromo-1,4-naphthoquinone and 2-amino-3-methoxy-1,4-naphthoquinone.
doi:10.3390/molecules18021973
PMCID: PMC3654863  PMID: 23381023
1,4-naphthoquinone; imide synthesis; sodium hydride-promoted bis-acylation; unsymmetrical imide
23.  Inhibition of Telomerase Activity by Oleanane Triterpenoid CDDO-Me in Pancreatic Cancer Cells is ROS-Dependent 
Molecules (Basel, Switzerland)  2013;18(3):3250-3265.
Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a synthetic derivative of oleanolic acid, a triterpene, with apoptosis-inducing activity in a wide range of cancer cells. Induction of apoptosis by CDDO-Me is associated with the generation of reactive oxygen species (ROS) and inhibition of telomerase activity. In the present study, we investigated the role of ROS in inhibition of telomerase by CDDO-me. Treatment of MiaPaCa-2 and Panc-1 pancreatic cancer cell lines with CDDO-Me induced the production of hydrogen peroxide and superoxide anions and inhibited the telomerase activity. Pretreatment of cells with N-acetylcycsteine, a general purpose antioxidant or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the telomerase inhibitory activity of CDDO-Me. Furthermore, blocking ROS generation also prevented the inhibition of hTERT gene expression, hTERT protein production and expression of a number of hTERT–regulatory proteins by CDDO-Me (e.g., c-Myc, Sp1, NF-κB and p-Akt). Data also showed that Akt plays an important role in the activation of telomerase activity. Together, these data suggest that inhibition of telomerase activity by CDDO-Me is mediated through a ROS-dependent mechanism; however, more work is needed to fully understand the role of ROS in down-regulation of hTERT gene and hTERT-regulatory proteins by CDDO-Me.
doi:10.3390/molecules18033250
PMCID: PMC3632053  PMID: 23486104
pancreatic cancer; CDDO-Me; ROS; hTERT; telomerase activity
24.  The Final Link: Tapping the Power of Chemical Genetics to Connect the Molecular and Biologic Functions of Mitotic Protein Kinases 
Molecules (Basel, Switzerland)  2012;17(10):12172-12186.
During mitosis, protein kinases coordinate cellular reorganization and chromosome segregation to ensure accurate distribution of genetic information into daughter cells. Multiple protein kinases contribute to mitotic regulation, modulating molecular signaling more rapidly than possible with gene expression. However, a comprehensive understanding of how kinases regulate mitotic progression remains elusive. The challenge arises from multiple functions and substrates, a large number of “bystander” phosphorylation events, and the brief window in which all mitotic events transpire. Analog-sensitive alleles of protein kinases are powerful chemical genetic tools for rapid and specific interrogation of kinase function. Moreover, combining these tools with advanced proteomics and substrate labeling has identified phosphorylation sites on numerous protein targets. Here, we review the chemical genetic tools available to study kinase function and identify substrates. We describe how chemical genetics can also be used to link kinase function with cognate phosphorylation events to provide mechanistic detail. This can be accomplished by dissecting subsets of kinase functions and chemical genetic complementation. We believe a complete “chemical genetic toolbox” will ultimately allow a comprehensive understanding of how protein kinases regulate mitosis.
doi:10.3390/molecules171012172
PMCID: PMC3620603  PMID: 23075814
chemical biology; protein kinases; separation of function; mitosis; cell division
25.  From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease 
Molecules (Basel, Switzerland)  2012;17(7):8312-8333.
Efforts to discover new drugs for Alzheimer’s disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1–42 induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1–42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer’s disease.
doi:10.3390/molecules17078312
PMCID: PMC3618987  PMID: 22781443
multifunction drugs; BACE1 inhibitor; anti-amyloid aggregation; chelator; antioxidant; neuroprotection

Results 1-25 (53)